Sulfonyl amide derivatives for the treatment of abnormal cell growth

ABSTRACT

The present invention relates to a compound of the formula I 
                         
wherein R 1  to R 6 , A, B, n and m are as defined herein. Such novel sulfonyl amide derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a Continuation of application Ser. No.15/492,719 filed Apr. 20, 2017, which is a Continuation of applicationSer. No. 15/263,041 filed Sep. 12, 2016, which is a Continuation ofapplication Ser. No. 15/000,944 filed Jan. 19, 2016 which isContinuation of application Ser. No. 14/552,153, filed Nov. 24, 2014,which is a Continuation of U.S. patent application Ser. No. 13/853,483,filed Mar. 29, 2013, which is a Continuation of U.S. patent applicationSer. No. 13/557,049, filed Jul. 24, 2012, issued May 14, 2013 as U.S.Pat. No. 8,440,822, which is a Continuation of U.S. patent applicationSer. No. 13/045,923, filed Mar. 11, 2011, issued Aug. 21, 2012 as U.S.Pat. No. 8,247,411, which is a Continuation of U.S. patent applicationSer. No. 12/105,151, filed Apr. 17, 2008, issued Apr. 19, 2011 as U.S.Pat. No. 7,928,109, which claims the benefit of priority to U.S.Provisional Patent Application No. 60/912,597, filed Apr. 18, 2007, thecontents of each of which are hereby incorporated by reference in theirentireties.

BACKGROUND OF THE INVENTION

This invention relates to novel sulfonyl amide derivatives that areuseful in the treatment of abnormal cell growth, such as cancer, inmammals. This invention also relates to a method of using such compoundsin the treatment of abnormal cell growth in mammals, especially humans,and to pharmaceutical compositions containing such compounds.

It is known that a cell may become cancerous by virtue of thetransformation of a portion of its DNA into an oncogene (i.e., a genewhich, on activation, leads to the formation of malignant tumor cells).Many oncogenes encode proteins that are aberrant tyrosine kinasescapable of causing cell transformation. Alternatively, theoverexpression of a normal proto-oncogenic tyrosine kinase may alsoresult in proliferative disorders, sometimes resulting in a malignantphenotype.

Receptor tyrosine kinases are enzymes which span the cell membrane andpossess an extracellular binding domain for growth factors such asepidermal growth factor, a transmembrane domain, and an intracellularportion which functions as a kinase to phosphorylate specific tyrosineresidues in proteins and hence to influence cell proliferation. Otherreceptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr,and VEGFR. It is known that such kinases are frequently aberrantlyexpressed in common human cancers such as breast cancer,gastrointestinal cancer such as colon, rectal or stomach cancer,leukemia, and ovarian, bronchial or pancreatic cancer. It has also beenshown that epidermal growth factor receptor (EGFR), which possessestyrosine kinase activity, is mutated and/or overexpressed in many humancancers such as brain, lung, squamous cell, bladder, gastric, breast,head and neck, oesophageal, gynecological and thyroid tumors.

Accordingly, it has been recognized that inhibitors of receptor tyrosinekinases are useful as selective inhibitors of the growth of mammaliancancer cells. For example, erbstatin, a tyrosine kinase inhibitor,selectively attenuates the growth in athymic nude mice of a transplantedhuman mammary carcinoma that expresses epidermal growth factor receptortyrosine kinase (EGFR) but is without effect on the growth of anothercarcinoma that does not express the EGF receptor. Thus, selectiveinhibitors of certain receptor tyrosine kinases, are useful in thetreatment of abnormal cell growth, in particular cancer, in mammals. Inaddition to receptor tyrosine kinases, selective inhibitors of certainnon-receptor tyrosine kinases, such as FAK (focal adhesion kinase), Ick,src, abl or serine/threonine kinases (e.g., cyclin dependent kinases),are useful in the treatment of abnormal cell growth, in particularcancer, in mammals. FAK is also known as the Protein-Tyrosine Kinase 2,PTK2.

Convincing evidence suggests that FAK, a cytoplasmic, non-receptortyrosine kinase, plays an essential role in cell-matrix signaltransduction pathways (Clark and Brugge 1995, Science 268: 233-239) andits aberrant activation is associated with an increase in the metastaticpotential of tumors (Owens et al. 1995, Cancer Research 55: 2752-2755).FAK was originally identified as a 125 kDa protein highlytyrosine-phosphorylated in cells transformed by v-Src. FAK wassubsequently found to be a tyrosine kinase that localizes to focaladhesions, which are contact points between cultured cells and theirunderlying substratum and sites of intense tyrosine phosphorylation. FAKis phosphorylated and, thus, activated in response to extracellularmatrix (ECM)-binding to integrins. Recently, studies have demonstratedthat an increase in FAK mRNA levels accompanied invasive transformationof tumors and attenuation of the expression of FAK (through the use ofantisense oligonucleotides) induces apoptosis in tumor cells (Xu et al.1996, Cell Growth and Diff. 7: 413-418). In addition to being expressedin most tissue types, FAK is found at elevated levels in most humancancers, particularly in highly invasive metastases.

Various compounds, such as styrene derivatives, have also been shown topossess tyrosine kinase inhibitory properties. Five European patentpublications, namely EP 0 566 226 A1 (published Oct. 20, 1993), EP 0 602851 A1 (published Jun. 22, 1994), EP 0 635 507 A1 (published Jan. 25,1995), EP 0 635 498 A1 (published Jan. 25, 1995), and EP 0 520 722 A1(published Dec. 30, 1992), refer to certain bicyclic derivatives, inparticular quinazoline derivatives, as possessing anti-cancer propertiesthat result from their tyrosine kinase inhibitory properties.

Also, World Patent Application WO 92/20642 (published Nov. 26, 1992),refers to certain bis-mono and bicyclic aryl and heteroaryl compounds astyrosine kinase inhibitors that are useful in inhibiting abnormal cellproliferation. World Patent Applications WO96/16960 (published Jun. 6,1996), WO 96/09294 (published Mar. 6, 1996), WO 97/30034 (published Aug.21, 1997), WO 98/02434 (published Jan. 22, 1998), WO 98/02437 (publishedJan. 22, 1998), and WO 98/02438 (published Jan. 22, 1998), also refer tosubstituted bicyclic heteroaromatic derivatives as tyrosine kinaseinhibitors that are useful for the same purpose. In addition, thefollowing list of publications relate to bis-mono and bicyclic aryl andheteroaryl compounds that may optionally be used as tyrosine kinaseinhibitors: WO 03/030909, WO 03/032997, US Patent ApplicationPublication No. 2003/0181474, US Patent Application Publication No.2003/0162802, U.S. Pat. No. 5,863,924, WO 03/078404, U.S. Pat. No.4,507,146, WO 99/41253, WO 01/72744, WO 02/48133, US Patent ApplicationPublication No. 2002/156087, WO 02/102783, and WO 03/063794.

U.S. Patent Application Publication No. 20040220177 relates to a broadclass of novel pyrimidine derivatives that are kinase inhibitors, andmore specifically, inhibitors of FAK. Moreover, U.S. Pat. No. 7,107,335relates more specifically to a subset of pyrimidine derivatives, i.e.,those bearing a 5-aminooxindole, which are tyrosine kinase inhibitors,and more particularly, FAK inhibitors. Compounds such as these areuseful in the treatment of abnormal cell growth.

Accordingly, a need exists for additional selective inhibitors ofcertain receptor and non-receptor tyrosine kinases, useful in thetreatment of abnormal cell growth, such as cancer, in mammals. Thepresent invention provides novel sulfonyl amide derivatives that arekinase inhibitors and inhibitors of the non-receptor tyrosine kinase,FAK, Aurora (e.g., Aurora-1 and Aurora-2), Pyk, HgK, and are useful inthe treatment of abnormal cell growth.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein

A is a ring moiety selected from the group consisting of a:

(a) 4- to 7-membered carbocyclyl,

(b) 4- to 7-membered heterocyclyl,

(c) phenyl, and

(d) 5- to 6-membered heteroaryl ring,

wherein each of said 4- to 7-membered carbocyclyl and 4- to 7-memberedheterocyclyl of said A group may optionally contain one or two olefinicbonds; and wherein one or two carbon ring atoms in each of said 4- to7-membered carbocyclyl and 4- to 7-membered heterocyclic of said A groupmay independently optionally be replaced with one or two moietiesindependently selected from the group consisting of —C(O)—, —C(S)— and—C(═NR⁴)—;

B is phenyl or a 5- to 6-membered heteroaryl;

K is CH, C(NH₂) or N;

each R¹ is independently selected from the group consisting of —H, halo,—CF₃, —CN, —NO₂, —NR⁷R⁸, —NR⁷C(NR⁷R⁸)(═CR⁹), —CR⁷(NR⁷R⁸)(═NR⁷),—NR⁷C(NR⁷R⁸)(═NR⁷), —NR⁷C(O)R⁹, —C(O)NR⁷R⁸, —C(O)R⁹, —C(O)C(O)R⁹,—C(O)OR¹⁰, —OC(O)R⁹, —OR¹⁰, —OC(O)OR¹⁰, —S(O)_(j)R¹¹, —S(O)(═NR⁷)R⁸,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₅-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₅-C₁₀)aryl and —(C₁-C₉)heteroarylmoieties of said R¹ is optionally independently substituted by one tothree R¹² groups;

R² and R³ are each independently selected from the group consisting of—H, -halo, —OR¹⁰, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R² and R³ is optionally substitutedby one to three R¹² groups;

R⁴ and R⁵ are each independently selected from the group consisting of—H, —NR⁷R⁸, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R⁴ and R⁵ is optionally substitutedby one to three R¹² groups;

R⁶ is selected from the group consisting of -halo, —NR⁷R⁸, —OR¹⁰,—C(O)R⁹, —CO₂R¹⁰, —CONR⁷R⁸, —S(O)_(j)R¹¹, —NR⁷CONR⁷R⁸, and —NR⁸SO₂R¹¹,—NO₂, —CN, —CF₃, —(C₁-C₉)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₂-C₆)perfluorinated alkyl, —(C₂-C₆)perfluorinated alkenyl,—(C₃-C₆)perfluorinated alkynyl, —(C₃-C₇)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₁-C₉)heterocyclyl, —(C₁-C₁₀)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,—(C₁-C₉)heteroaryl, —(C₆-C₁₀)perfluorinated aryl, and—(C₁-C₉)perfluorinated heteroaryl; and wherein each of said—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₇)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₁-C₉)heterocyclyl, —(C₁-C₁₀)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆—C)heterobicycloalkenyl, —(C₆-C₀₁)aryl,and —(C₁-C₉)heteroaryl moieties of said R⁶ is optionally substituted byone to three R¹² groups;

R⁷ and R⁸ are each independently selected from the group consisting of—H, —OR¹⁰, —S(O)_(j)R¹¹, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R⁷ and R⁸ is optionally substituted by one to three R¹² groups;

each R⁹ is independently selected from the group consisting of —H,-halo, —NR¹³R¹⁴, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl,—(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, (C₄-C₀)heterocycloalkenyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R⁹ is optionally substituted by oneto three R¹² groups;

each R¹⁰ is independently selected from the group consisting of —H,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R¹⁰ is optionally substituted by one to three R¹² groups;

each R¹¹ is independently selected from the group consisting of —H,—NR¹³R¹⁴, —C(O)R¹³, —CF₃, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; land wherein each of the foregoing—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R¹¹ is optionally substituted by one to three R¹² groups;

each R¹² is independently selected from the group consisting of —H,—OR¹³, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —OC(O)OR¹³, —C(O)NR¹³R¹⁴,—NR¹³C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —NR¹³C(NR¹³R¹⁴)(═NR¹³),—NR¹³C(NR¹³R¹⁴)(═N—C(O)R¹³), —NR¹³C(O)R¹⁴, —NR¹³S(O)_(j)R¹³,—S(O)_(j)R¹³, —CF₃, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹² is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)R¹⁵, —C(O)NR¹⁵R¹⁶,—S(O)_(j)R¹⁵, and —S(O)_(j)NR¹⁵R¹⁶, —(C₃-C₁₀)cycloalkyl,—(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl), —NH₂, —NH((C₁-C₆)alkyl)and —N((C₁-C₆)alkyl)₂; R¹³ and R¹⁴ are each independently selected fromthe group consisting of —H, —NR¹⁵C(O)R¹⁶, —CF₃, —CN, —S(O)_(j)R¹⁵,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₅-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹³ and R¹⁴ is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl),—(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl),—NH₂, —NH((C₁-C₆)alkyl) and —N((C₁-C₆)alkyl)₂;

R¹⁵ and R¹⁶ are each independently selected from the group consisting of—H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl,—(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹⁵ and R¹⁶ is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl),—(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl),—NH₂, —NH((C₁-C₆)alkyl) and —N((C₁-C₆)alkyl)₂;

wherein one or two carbon ring atoms in each of the aforementioned—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl and —(C₆-C₉)heterobicycloalkenyl in saidR¹-R¹⁴ groups may optionally and independently be replaced with —C(O)—or —C(S)—;

wherein two groups attached to the same tetravalent carbon atom in eachof the aforementioned —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl and—(C₆-C₉)heterobicycloalkeny of said R¹ to R¹⁴ groups may optionally jointo form a ring system selected from the group consisting of a—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,and —(C₄-C₉)heterocycloalkenyl; and wherein

j is an integer from 0 to 2;

n is an integer from 1 to 3; and

m is an integer from 0 to 3.

In one embodiment, the invention relates to a compound of formula Iwherein A is a 4- to 7-membered carbocyclyl; and wherein saidcarbocyclyl may additionally contain one or two olefinic bonds.

In another embodiment, the invention relates to a compound of formula Iwherein A is a 4- to 7-membered carbocyclyl selected from the groupconsisting of cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclopentendienyl, cyclohexyl, cyclohexenyl,cyclohexadienyl, cycloheptyl, cycloheptenyl, and cycloheptadienyl.

In another embodiment, the invention relates to a compound of formula Iwherein A is a 4- to 7-membered heterocyclyl, and wherein said 4- to7-membered heterocyclyl may additionally contain one or two olefinicbonds.

In another embodiment, the invention relates to a compound of formula Iwherein A is a 4- to 7-membered heterocyclyl selected from the groupconsisting of azetidinyl, oxetanyl, pyrrolidynyl, dihydropyrazolyl,tetrahydropyrazolyl, dihydrofuranyl, tetradydrofuranyl,dihydrothiophenyl, tetra hydrothiopenyl, dihydropyridinyl,tetrahydropyridinyl, piperidinyl, piperazinyl, pyranyl, dihydropyranyl,tetrahydropyranyl, thiopyrianyl, dihydrothiopyranyl,tetrahydrothiopyranyl, morpholinyl, dihydroazepinyl, tetrahydroazepinyl,dihyrooxepinyl, tetrahydrooxepinyl, oxepanyl, dihyrothiepinyl,tetrahydrothiepinyl and thiepanyl.

In another embodiment, the invention relates to a compound of formula Iwherein A is a phenyl.

In another embodiment, the invention relates to a compound of formula Iwherein A is a 5- to 6-membered heteroaryl.

In another embodiment, the invention relates to a compound of formula Iwherein A is a 5- to 6-membered heteroaryl selected from the groupconsisting of furanyl, pyrrolyl, thiopenyl, thiazolyl, isothiazolyl,pyrazolyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, oxadiazoyl, thiadiazoyl, and benzothiazole, benzooxazole.

In one embodiment, the invention relates to a compound of formula Iwherein each R¹ is independently selected from the group consisting of—H, halo, —CF₃, —CN, —NO₂, —NR⁷R⁸, —NR⁷C(NR⁷R⁸)(═CR⁹),—CR⁷(NR⁷R⁸)(═NR⁷), —NR⁷C(NR⁷R⁸)(═NR⁷), —NR⁷C(O)R⁹, —C(O)NR⁷R⁸, —C(O)R⁹,—C(O)C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —OR¹⁰, —OC(O)OR¹⁰, —S(O)_(j)R¹¹, and—S(O)(═NR⁷)R⁸.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —S(O)_(j)R¹¹.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —S(O)_(j)R¹¹, and R¹¹ is selected from the groupconsisting of —H, —NR¹³R¹⁴ and —(C₁-C₆)alkyl; and wherein said—(C₁-C₆)alkyl of said R¹¹ is optionally independently substituted by oneto three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —C(O)OR¹⁰.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —C(O)OR¹⁰ and R¹⁰ is —(C₁-C₆)alkyl optionally substitutedby one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —C(O)R⁹.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —C(O)R⁹ and R⁹ is selected from the group consisting of—NR¹³R¹⁴, —(C₁-C₆)alkyl and —(C₃-C₁₀)cycloalkyl; wherein each of said—(C₁-C₆)alkyl, and —(C₃-C₁₀)cycloalkyl of said R⁹ group is optionallysubstituted by one to three R¹² groups; and wherein two groups attachedto the same tetravalent carbon atom of said —(C₁-C₆)alkyl and—(C₃-C₁₀)cycloalkyl of said R⁹ may optionally join to form a ring systemselected from the group consisting of a —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl, and—(C₄-C₉)heterocycloalkenyl.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —C(O)R⁹, and R⁹ is —(C₁-C₆)alkyl optionally substituted bya group selected from the group consisting of —NR¹³R¹⁴, —NR¹⁵C(O)R¹⁶ and—CF₃.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —C(O)R⁹, and R⁹ is —NR¹³R¹⁴.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —C(O)R⁹, R⁹ is —NR¹³R¹⁴, and R¹³ and R¹⁴ are eachindependently selected from the group consisting of —H and—(C₁-C₆)alkyl; and wherein said —(C₁-C₆)alkyl of said R¹³ and R¹⁴ groupsis optionally independently substituted with one to three groupsselected from the group consisting of -halo, —CF₃, —CN, —NO₂, —OH,—O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl), —(C₃-C₁₀)cycloalkyl,—(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl), —NH₂, —NH((C₁-C₆)alkyl)and —N((C₁-C₆)alkyl)₂.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —C(O)R⁹, R⁹ is —NR¹³R¹⁴, and R¹³ and R¹⁴ are eachindependently selected from the group consisting —H and —(C₁-C₆)alkyl;wherein said —(C₁-C₆)alkyl of said R¹³ and R¹⁴ are each optionallyindependently substituted with one to three groups selected from thegroup consisting of —(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl,—(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; and wherein each of said—(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —(C₆-C₁₀)aryl, and—(C₁-C₉)heteroaryl optional substituents of said —(C₁-C₆)alkyl of saidR¹³ and R¹⁴ is optionally independently substituted by one to threegroups selected from the group consisting of -halo, —CF₃, —CN, —NO₂,—OH, —O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl), —(C₃-C₁₀)cycloalkyl,—(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl), —NH₂, —NH((C₁-C₆)alkyl)and —N((C₁-C₆)alkyl)₂.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —C(O)R⁹, R⁹ is —NR¹³R¹⁴, and R¹³ and R¹⁴ are eachindependently selected from the group consisting of —(C₃-C₁₀)cycloalkyland —(C₂-C₉)heterocycloalkyl, —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; andwherein each of said —(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl,—(C₆-C₁₀)aryl, and -(C₁-C₉)heteroaryl of said R¹³ and R¹⁴ is optionallyindependently substituted by one to three groups independently selectedfrom the group consisting of -halo, —CF₃, —CN, —NO₂, —OH,—O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl), —(C₃-C₁₀)cycloalkyl,—(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl), —NH₂, —NH((C₁-C₆)alkyl)and —N((C₁-C₆)alkyl)₂.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —C(O)R⁹, and R⁹ is selected from the group consisting of—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl and—(C₆-C₉)heterobicycloalkenyl; and wherein each of the foregoing—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl and(C₄-C₉)heterocycloalkenyl moieties of said R⁹ is optionallyindependently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —C(O)R⁹, and R⁹ is selected from the group consisting of—(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; and wherein each of the foregoing—(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moieties of said R⁹ is optionallyindependently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —NR⁷R⁸.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —NR⁷R⁸, and R⁷ and R⁸ are each independently selected fromthe group consisting of —H, —CF₃ and —S(O)_(j)R¹¹.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —NR⁷R⁸, and R⁷ and R⁸ are each independently selected fromthe group consisting of —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl and—(C₂-C₆)alkynyl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl moieties of said R⁷ and R⁸ isoptionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —NR⁷C(O)R⁹.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —NR⁷C(O)R⁹ and R⁷ is selected from the group consisting of—H and —(C₁-C₆)alkyl; and wherein said —(C₁-C₆)alkyl of said R⁷ isoptionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —NR⁷C(O)R⁹ and R⁷ is selected from the group consisting of—H and —(C₁-C₆)alkyl; and wherein said —(C₁-C₆)alkyl of said R⁷ isoptionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —NR⁷C(O)R⁹, and R⁹ is selected from the group consistingof —H and —S(O)_(j)R¹¹.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —NR⁷C(O)R⁹, and R⁹ is selected from the group consistingof —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl; and wherein said—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl of said R⁹ isoptionally independently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —NR⁷C(O)R⁹ and R^(9 is) —(C₁-C₆)alkyl; wherein said—(C₁-C₆)alkyl of said R⁹ is optionally independently substituted by oneto three R¹² groups; and wherein two groups attached to the sametetravalent carbon atom of said —(C₁-C₆)alkyl of said R⁹ may optionallyjoin to form a ring system selected from the group consisting of a—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,and —(C₄-C₉)heterocycloalkenyl.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —NR⁷C(O)R⁹ and R⁹ is —(C₁-C₆)alkyl; and wherein said—(C₁-C₆)alkyl of said R⁹ is substituted by one to three R¹² groupsindependently selected from the group consisting of —OR¹³, —C(O)R¹³,—C(O)OR¹³, —OC(O)R¹³, —OC(O)OR¹³, —C(O)NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴,—NR¹³R¹⁴, —NR¹³C(NR¹³R¹⁴)(═NR¹³), —NR¹³C(NR¹³R¹⁴)(═N—C(O)R¹³),—NR¹³C(O)R¹⁴, —NR¹³S(O)_(j)R¹³, —S(O)_(j)R¹³, —CF₃, and —CN.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —NR⁷C(O)R⁹ and R⁹ is —(C₁-C₆)alkyl, wherein said—(C₁-C₆)alkyl of said R⁹ is substituted by one to three R¹² groupsindependently selected from the group consisting of —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —NR⁷C(O)R⁹ and R⁹ is —(C₁-C₆)alkyl; wherein said—(C₁-C₆)alkyl of said R⁹ is substituted by one to three R¹² groupsindependently selected from the group consisting of —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl and —(C₆-C₉)heterobicycloalkenyl; and whereineach of the foregoing —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl and —(C₆-C₉)heterobicycloalkenyl of said R¹²is optionally independently substituted by one to three groupsindependently selected from the group consisting of -halo, —CF₃, —CN,—NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl), —(C₃-C₁₀)cycloalkyl,—(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl), —NH₂, —NH((C₁-C₆)alkyl)and —N((C₁-C₆)alkyl)₂.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —NR⁷C(O)R⁹ and R⁹ is —(C₁-C₆)alkyl; wherein said—(C₁-C₆)alkyl of said R⁹ is substituted by one to three R¹² groupsindependently selected from the group consisting of —(C₆-C₁₀)aryl, and—(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl of said R¹² is optionally independently substitutedby one to three groups selected from the group consisting of -halo,—CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl),—(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl),—NH₂, —NH((C₁-C₆)alkyl) and —N((C₁—C)alkyl)₂.

In another embodiment, the invention relates to a compound of formula Iwherein each R¹ is independently selected from the group consisting of—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₂-C₆)alkynyl; and wherein each ofthe foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl and —(C₂-C₆)alkynylmoieties of said R¹ is optionally independently substituted by one tothree R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —(C₁-C₆)alkyl optionally independently substituted by oneto three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein each R¹ is —(C₁-C₁₀)alkyl is independently substituted with agroup selected from the group consisting of R¹³, —S(O)_(j)R¹³, and—NR¹³S(O)_(j)R¹³.

In another embodiment, the invention relates to a compound of formula Iwherein each R¹ is independently selected from the group consisting of—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl and—(C₆-C₉)heterobicycloalkenyl; and wherein each of the foregoing—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl and—(C₄-C₉)heterocycloalkenyl moieties of said R¹ is optionallyindependently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is selected from the group consisting of—(C₂-C₉)heterocycloalkyl; and wherein said —(C₂-C₉)heterocycloalkyl ofsaid R¹ is optionally independently substituted by one to three R¹²groups.

In another embodiment, the invention relates to a compound of formula Iwherein each R¹ is independently selected from the group consisting of—(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl; and wherein each of the foregoing—(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl of said R¹ moieties is optionallyindependently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —S(O)₂NR¹³R¹⁴.

In one embodiment, the invention relates to a compound of formula Iwherein R² and R³ are each independently selected from the groupconsisting of —H, -halo, and —OR¹⁰.

In another embodiment, the invention relates to a compound of formula Iwherein R² and R³ are each independently selected from the groupconsisting of —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₂-C₆)alkynyl;and wherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and—(C₂-C₆)alkynyl moieties of said R² and R³ is optionally independentlysubstituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R² and R³ are each independently selected from the groupconsisting of —H, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, and —(C₄-C₉)heterocycloalkenyl; and whereineach of the foregoing —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, and —(C₄-C₉)heterocycloalkenyl moieties ofsaid R² and R³ is optionally independently substituted by one to threeR¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R² and R³ are each independently selected from the groupconsisting of —H, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl; and wherein eachof the foregoing —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moieties of saidR² and R³ is optionally independently substituted by one to three R¹²groups.

In one embodiment, the invention relates to a compound of formula Iwherein R⁴ and R⁵ are each independently selected from the groupconsisting of —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₂-C₆)alkynyl;and wherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl and—(C₂-C₆)alkynyl moieties of said R⁴ and R⁵ is optionally independentlysubstituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R⁴ and R⁵ are each independently selected from the groupconsisting of —H, —(C₁-C₆)alkyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl and—(C₄-C₉)heterocycloalkenyl; and wherein each of the foregoing—(C₁-C₆)alkyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, and —(C₄-C₉)heterocycloalkenyl moieties ofsaid R⁴ and R⁵ is optionally independently substituted by one to threeR¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R⁴ and R⁵ are each independently selected from the groupconsisting of —H, —(C₁-C₆)alkyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl;and wherein each of the foregoing —(C₁-C₆)alkyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R⁴ and R⁵ is optionallyindependently substituted by one to three R¹² groups.

In one embodiment, the invention relates to a compound of formula Iwherein the moiety

represents a moiety selected from the group consisting of:

In one embodiment, the invention relates to a compound of formula Iwherein R⁶ is selected from the group consisting of —NR⁷R⁸, —OR¹⁰,—C(O)R⁹, —CO₂R¹⁰, —CONR⁷R⁸, —S(O)_(j)R¹¹, —NR⁷CONR⁷R⁸, —NR⁸SO₂R¹¹—NO₂,—CN and —CF₃.

In another embodiment, the invention relates to a compound of formula Iwherein R⁶ is selected from the group consisting of —CF₃, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₂-C₆)perfluorinated alkyl,—(C₂-C₆)perfluorinated alkenyl, and —(C₃-C₆)perfluorinated alkynyl; andwherein each of said —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynylmoieties of said R⁶ is optionally independently substituted by one tothree R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R⁶ is —CF₃.

In another embodiment, the invention relates to a compound of formula Iwherein R⁶ is selected from the group consisting of —(C₃-C₇)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₁-C₉)heterocyclyl, —(C₁-C₁₀)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, and —(C₆-C₉)heterobicycloalkenyl; andwherein each of said —(C₃-C₇)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl, —(C₁-C₉)heterocyclyl,—(C₁-C₁₀)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl, and—(C₆-C₉)heterobicycloalkenyl moieties of said R⁶ is optionallyindependently substituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iwherein R⁶ is selected from the group consisting of —(C₆-C₁₀)aryl,—(C₁-C₉)heteroaryl, —(C₆-C₁₀)perfluorinated aryl and—(C₁-C₉)perfluorinated heteroaryl; and wherein each of said—(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moieties of said R⁶ is optionallyindependently substituted by one to three R¹² groups.

In one embodiment, the invention relates to a compound of formula Iwherein K is CH.

In another embodiment, the invention relates to a compound of formula Iwherein K is C(NH₂).

In another embodiment, the invention relates to a compound of formula Iwherein K is N.

In one embodiment, the invention relates to a compound of formula Iwherein m is 1.

In another embodiment, the invention relates to a compound of formula Iwherein m is 0.

In one embodiment, the invention relates to a compound of formula Iwherein n is 1.

In another embodiment, the invention relates to a compound of formula Iwherein n is 2.

In another embodiment, the invention relates to a compound of formula Iwherein n is 3.

In one embodiment, the invention relates to a compound of formula Iwherein K is CH, n is 1, and R₆ is —CF₃.

In one embodiment, the invention relates to a compound of formula Iwherein K is CH, n is 2, and R₆ is —CF₃.

The present invention also provides a compound of formula Ia:

or a pharmaceutically acceptable salt thereof; wherein

A is phenyl;

B is phenyl or a 5- to 6-membered heteroaryl;

K is CH, C(NH₂) or N;

each R¹ is independently selected from the group consisting of —H, halo,—CF₃, —CN, —NO₂, —NR⁷R⁸, —NR⁷C(NR⁷R⁸)(═CR⁹), —CR⁷(NR⁷R⁸)(═NR⁷),—NR⁷C(NR⁷R⁸)(═NR⁷), —NR⁷C(O)R⁹, —C(O)NR⁷R⁸, —C(O)R⁹, —C(O)C(O)R⁹,—C(O)OR¹⁰, —OC(O)R⁹, —OR¹⁰, —OC(O)OR¹⁰, —S(O)_(j)R¹¹, —S(O)(═NR⁷)R⁸,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₁-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroarylmoieties of said R¹ is optionally independently substituted by one tothree R¹² groups;

R² and R³ are each independently selected from the group consisting of—H, -halo, —OR¹⁰, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R² and R³ is optionally substitutedby one to three R¹² groups;

R⁴ and R⁵ are each independently selected from the group consisting of—H, —NR⁷R⁸, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R⁴ and R⁵ is optionally substitutedby one to three R¹² groups;

R⁶ is selected from the group consisting of -halo, —NR⁷R⁸, —OR¹⁰,—C(O)R⁹, —CO₂R¹⁰, —CONR⁷R⁸, —S(O)_(j)R¹¹, —NR⁷CONR⁷R⁸, and —NR⁸SO₂R¹¹,—NO₂, —CN, —CF₃, —(C₁-C₁₀)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₂-C₆)perfluorinated alkyl, —(C₂-C₆)perfluorinated alkenyl,—(C₃-C₆)perfluorinated alkynyl, —(C₃-C₇)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₁-C₉)heterocyclyl, —(C₁-C₁₀)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,—(C₁-C₉)heteroaryl, —(C₆-C₁₀)perfluorinated aryl, and—(C₁-C₉)perfluorinated heteroaryl; and wherein each of said—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₇)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₁-C₉)heterocyclyl, —(C₁-C₁₀)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl moieties of said R⁶ is optionally substituted byone to three R¹² groups; R⁷ and R⁸ are each independently selected fromthe group consisting of —H, —OR¹⁰, —S(O)_(j)R¹¹, —NO₂, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R⁷ and R⁸ is optionally substituted by one to three R¹² groups;

each R⁹ is independently selected from the group consisting of —H,-halo, —NR¹³R¹⁴, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₅-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl,—(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁—C)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R⁹ is optionally substituted by oneto three R¹² groups;

each R¹⁰ is independently selected from the group consisting of —H,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R¹⁰ is optionally substituted by one to three R¹² groups;

each R¹¹ is independently selected from the group consisting of —H,—NR¹³R¹⁴, —C(O)R¹³, —CF₃, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; land wherein each of the foregoing—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R¹¹ is optionally substituted by one to three R¹² groups;

each R¹² is independently selected from the group consisting of —H,—OR¹³, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —OC(O)OR¹, —C(O)NR¹³R¹⁴,—NR¹³C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —NR¹³C(NR¹³R¹⁴)(═NR¹³),—NR¹³C(NR¹³R¹⁴)(═N—C(O)R¹³), —NR¹³C(O)R¹⁴, —NR¹³S(O)_(j)R¹³,—S(O)_(j)R¹³, —CF₃, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹² is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)R¹⁵, —C(O)NR¹⁵R¹⁶,—S(O)_(j)R¹⁵, and —S(O)_(j)NR¹⁵R¹⁶, —(C₃-C₁₀)cycloalkyl,—(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl), —NH₂, —NH((C₁-C₆)alkyl)and —N((C₁-C₆)alkyl)₂;

R¹³ and R¹⁴ are each independently selected from the group consisting of—H, —NR⁵C(O)R¹⁶, —CF₃, —CN, —S(O)_(j)R¹⁵, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₆)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹³ and R¹⁴ is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl),—(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl),—NH₂, —NH((C₁-C₆)alkyl) and —N((C₁-C₆)alkyl)₂;

R¹⁵ and R¹⁶ are each independently selected from the group consisting of—H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl,—(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₁₀)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl,—(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl of said R¹⁵ and R¹⁶ is optionallyindependently substituted by one to three groups selected from the groupconsisting of -halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl),—C(O)((C₁-C₆)alkyl), —(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —SH,—S((C₁-C₆)alkyl), —NH₂, —NH((C₁-C₆)alkyl) and —N((C₁-C₆)alkyl)₂;

wherein one or two carbon ring atoms in each of the aforementioned—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl and —(C₆-C₉)heterobicycloalkenyl in saidR¹-R¹⁴ groups may optionally and independently be replaced with —C(O)—or —C(S)—;

wherein two groups attached to the same tetravalent carbon atom in eachof the aforementioned —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl and—(C₆-C₉)heterobicycloalkeny of said R¹ to R¹⁴ groups may optionally jointo form a ring system selected from the group consisting of a—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,and —(C₄-C₉)heterocycloalkenyl; and wherein

j is an integer from 0 to 2;

n is an integer from 1 to 3; and

m is an integer from 0 to 3.

In another embodiment, the invention relates to a compound of formula Iawherein at least one R¹ is —C(O)OR¹⁰.

In another embodiment, the invention relates to a compound of formula Iawherein at least one R¹ is —C(O)OR¹⁰ and R¹⁰ is —(C₁-C₆)alkyl optionallysubstituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iawherein at least one R¹ is —C(O)R⁹.

In another embodiment, the invention relates to a compound of formula Iawherein at least one R¹ is —C(O)R⁹ and R⁹ is selected from the groupconsisting of —NR¹³R¹⁴, —(C₁-C₆)alkyl and —(C₃-C₁₀)cycloalkyl; whereineach of said —(C₁-C₆)alkyl, and —(C₃-C₁₀)cycloalkyl of said R⁹ group isoptionally substituted by one to three R¹² groups; and wherein twogroups attached to the same tetravalent carbon atom of said—(C₁-C₆)alkyl and —(C₃-C₁₀)cycloalkyl of said R⁹ may optionally join toform a ring system selected from the group consisting of a—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,and —(C₄-C₉)heterocycloalkenyl.

In another embodiment, the invention relates to a compound of formula Iawherein at least one R¹ is —C(O)R⁹ and R⁹ is —(C₁-C₆)alkyl optionallysubstituted by a group selected from the group consisting of —NR¹³R¹⁴,—NR¹⁵C(O)R¹⁶ and —CF₃.

In another embodiment, the invention relates to a compound of formula Iawherein at least one R¹ is —C(O)R⁹ and R⁹ is —NR¹³R¹⁴.

In another embodiment, the invention relates to a compound of formula Iawherein at least one R¹ is —C(O)R⁹, R⁹ is —NR¹³R¹⁴, and R¹³ and R¹⁴ areeach independently selected from the group consisting of —H and—(C₁-C₆)alkyl; and wherein said —(C₁-C₆)alkyl of said R¹³ and R¹⁴ groupsis optionally independently substituted with one to three groupsselected from the group consisting of -halo, —CF₃, —CN, —NO₂, —OH,—O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl), —(C₅-C₁₀)cycloalkyl,—(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl), —NH₂, —NH((C₁-C₆)alkyl)and —N((C₁-C₆)alkyl)₂.

In another embodiment, the invention relates to a compound of formula Iawherein at least one R¹ is —C(O)R⁹, R⁹ is —NR¹³R¹⁴, and R¹³ and R¹⁴ areeach independently selected from the group consisting —H and—(C₁-C₆)alkyl; wherein said —(C₁-C₆)alkyl of said R¹³ and R¹⁴ are eachoptionally independently substituted with one to three groups selectedfrom the group consisting of —(C₃-C₁₀)cycloalkyl,—(C₂-C₉)heterocycloalkyl, —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; andwherein each of said —(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl,—(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl optional substituents of said—(C₁-C₆)alkyl of said R¹³ and R¹⁴ is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl),—(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl),—NH₂, —NH((C₁-C₆)alkyl) and —N((C₁-C₆)alkyl)₂.

In another embodiment, the invention relates to a compound of formula Iawherein m is 1.

The present invention also provides a compound of formula Ib:

or a pharmaceutically acceptable salt thereof; wherein

A is phenyl;

B is phenyl or a 5- to 6-membered heteroaryl;

K is CH, C(NH₂) or N;

at least one R¹ is —(C₁-C₆)alkyl optionally independently substituted byone to three R¹² groups;

R² and R³ are each independently selected from the group consisting of—H, -halo, —OR¹⁰, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₆)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R² and R³ is optionally substitutedby one to three R¹² groups;

R⁴ and R⁵ are each independently selected from the group consisting of—H, —NR⁷R⁸, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R⁴ and R⁵ is optionally substitutedby one to three R¹² groups;

R⁶ is selected from the group consisting of -halo, —NR⁷R⁸, —OR¹⁰,—C(O)R⁹, —CO₂R¹⁰, —CONR⁷R⁸, —S(O)_(j)R¹¹, —NR⁷CONR⁷R⁸, and —NR⁸SO₂R¹¹,—NO₂, —CN, —CF₃, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₂-C₆)perfluorinated alkyl, —(C₂-C₆)perfluorinated alkenyl,—(C₃-C₆)perfluorinated alkynyl, —(C₃-C₇)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₁-C₉)heterocyclyl, —(C₁-C₁₀)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,—(C₁-C₉)heteroaryl, —(C₆-C₁₀)perfluorinated aryl, and—(C₁-C₉)perfluorinated heteroaryl; and wherein each of said—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₇)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₁-C₉)heterocyclyl, —(C₁-C₁₀)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl moieties of said R⁶ is optionally substituted byone to three R¹² groups;

R⁷ and R⁸ are each independently selected from the group consisting of—H, —OR¹⁰, —S(O)_(j)R¹¹, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R⁷ and R⁸ is optionally substituted by one to three R¹² groups;

each R⁹ is independently selected from the group consisting of —H,-halo, —NR¹³R¹⁴, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)Cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl,—(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R⁹ is optionally substituted by oneto three R¹² groups;

each R¹⁰ is independently selected from the group consisting of —H,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R¹⁰ is optionally substituted by one to three R¹² groups;

each R¹¹ is independently selected from the group consisting of —H,—NR¹³R¹⁴, —C(O)R¹³, —CF₃, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; land wherein each of the foregoing—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R¹¹ is optionally substituted by one to three R¹² groups;

each R¹² is independently selected from the group consisting of —H,—OR¹³, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —OC(O)OR¹³, —C(O)NR¹³R¹⁴,—NR¹³C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —NR¹³C(NR¹³R¹⁴)(═NR¹³),—NR¹³C(NR¹³R¹⁴)(═N—C(O)R¹³), —NR¹³C(O)R¹⁴, —NR¹³S(O)_(j)R¹³,—S(O)_(j)R¹³, —CF₃, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹² is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)R¹⁵, —C(O)NR¹⁵R¹⁶,—S(O)_(j)R¹⁵, and —S(O)_(j)NR¹⁵R¹⁶, —(C₃-C₁₀)cycloalkyl,—(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl), —NH₂, —NH((C₁-C₆)alkyl)and —N((C₁-C₆)alkyl)₂;

R¹³ and R¹⁴ are each independently selected from the group consisting of—H, —NR¹⁵C(O)R¹⁶, —CF₃, —CN, —S(O)_(j)R¹⁵, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹³ and R¹⁴ is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl),—(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl),—NH₂, —NH((C₁-C₆)alkyl) and —N((C₁-C₆)alkyl)₂;

R¹⁵ and R¹⁶ are each independently selected from the group consisting of—H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl,—(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹ and R¹⁶ is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl),—(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl),—NH₂, —NH((C₁-C₆)alkyl) and —N((C₁-C₆)alkyl)₂;

wherein one or two carbon ring atoms in each of the aforementioned—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl and —(C₆-C₉)heterobicycloalkenyl in saidR¹-R¹⁴ groups may optionally and independently be replaced with —C(O)—or —C(S)—;

wherein two groups attached to the same tetravalent carbon atom in eachof the aforementioned —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl and—(C₆-C₉)heterobicycloalkeny of said R¹ to R¹⁴ groups may optionally jointo form a ring system selected from the group consisting of a—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,and —(C₄-C₉)heterocycloalkenyl; and wherein

j is an integer from 0 to 2;

n is an integer from 1 to 3; and

m is an integer from 0 to 3.

In another embodiment, the invention relates to a compound of formula Iaor 1b wherein R² and R³ are each independently selected from the groupconsisting of —H, -halo, and —OR¹⁰.

In another embodiment, the invention relates to a compound of formula Iaor 1b wherein R⁴ and R⁵ are each independently selected from the groupconsisting of —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, and —(C₂-C₆)alkynyl;and wherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl and—(C₂-C₆)alkynyl moieties of said R⁴ and R⁵ is optionally independentlysubstituted by one to three R¹² groups.

In another embodiment, the invention relates to a compound of formula Iaor 1b wherein R⁶ is —CF₃.

In another embodiment, the invention relates to a compound of formula Iaor 1b wherein K is CH.

In another embodiment, the invention relates to a compound of formula Iaor 1b wherein m is 1.

In another embodiment, the invention relates to a compound of formula Iaor 1b wherein n is 1.

The present invention provides a compound of formula Ic:

or a pharmaceutically acceptable salt thereof; wherein the moiety

represents a moiety selected from the group consisting of:

A is a ring moiety selected from the group consisting of a:

(a) 4- to 7-membered carbocyclyl,

(b) 4- to 7-membered heterocyclyl,

(c) phenyl, and

(d) 5- to 6-membered heteroaryl ring,

wherein each of said 4- to 7-membered carbocyclyl and 4- to 7-memberedheterocyclyl of said A group may optionally contain one or two olefinicbonds; and wherein one or two carbon ring atoms in each of said 4- to7-membered carbocyclyl and 4- to 7-membered heterocyclic of said A groupmay independently optionally be replaced with one or two moietiesindependently selected from the group consisting of —C(O)—, —C(S)— and—C(═NR⁴)—;

K is CH, C(NH₂) or N;

each R¹ is independently selected from the group consisting of —H, halo,—CF₃, —CN, —NO₂, —NR⁷R⁸, —NR⁷C(NR⁷R⁸)(═CR⁹), —CR⁷(NR⁷R⁸)(═NR⁷),—NR⁷C(NR⁷R⁸)(═NR⁷), —NR⁷C(O)R⁹, —C(O)NR⁷R⁸, —C(O)R⁹, —C(O)C(O)R⁹,—C(O)OR¹⁰, —OC(O)R⁹, —OR¹⁰, —OC(O)OR¹⁰, —S(O)_(j)R¹¹, —S(O)(═NR⁷)R⁸,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroarylmoieties of said R¹ is optionally independently substituted by one tothree R¹² groups;

R⁶ is selected from the group consisting of -halo, —NR⁷R⁸, —OR¹⁰,—C(O)R⁹, —CO₂R¹⁰, —CONR⁷R⁸, —S(O)_(j)R¹¹, —NR⁷CONR⁷R⁸, and —NR⁸SO₂R¹¹,—NO₂, —CN, —CF₃, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₂-C₆)perfluorinated alkyl, —(C₂-C₆)perfluorinated alkenyl,—(C₃-C₆)perfluorinated alkynyl, —(C₃-C₇)Cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₁-C₉)heterocyclyl, —(C₁-C₁₀)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,—(C₁-C₉)heteroaryl, —(C₆-C₁₀)perfluorinated aryl, and—(C₁-C₉)perfluorinated heteroaryl; and wherein each of said—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₇)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₁-C₉)heterocyclyl, —(C₁-C₁₀)heterocycloalkenyl,—(C₅-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl moieties of said R⁶ is optionally substituted byone to three R¹² groups;

R⁷ and R⁸ are each independently selected from the group consisting of—H, —OR¹⁰, —S(O)_(j)R¹¹, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R⁷ and R⁸ is optionally substituted by one to three R¹² groups;

each R⁹ is independently selected from the group consisting of —H,-halo, —NR¹³R¹⁴, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl,—(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R⁹ is optionally substituted by oneto three R¹² groups;

each R¹⁰ is independently selected from the group consisting of —H,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R¹⁰ is optionally substituted by one to three R¹² groups;

each R¹¹ is independently selected from the group consisting of —H,—NR¹³R¹⁴, —C(O)R¹³, —CF₃, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; land wherein each of the foregoing—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R¹¹ is optionally substituted by one to three R¹² groups;

each R¹² is independently selected from the group consisting of —H,—OR¹³, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —OC(O)OR¹³, —C(O)NR¹³R¹⁴,—NR¹³C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —NR¹³C(NR¹³R¹⁴)(═NR¹³),—NR¹³C(NR¹³R¹⁴)(═N—C(O)R¹³), —NR¹³C(O)R¹⁴, —NR¹³S(O)_(j)R¹³,—S(O)_(j)R¹³, —CF₃, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹² is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)R¹⁵, —C(O)NR¹⁵R¹⁶,—S(O)_(j)R¹⁵, and —S(O)_(j)NR¹⁵R¹⁶, —(C₃-C₁₀)cycloalkyl,—(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl), —NH₂, —NH((C₁-C₆)alkyl)and —N((C₁-C₆)alkyl)₂;

R¹³ and R¹⁴ are each independently selected from the group consisting of—H, —NR¹⁵C(O)R¹⁶, —CF₃, —CN, —S(O)_(j)R¹⁵, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹³ and R¹⁴ is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl),—(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl),—NH₂, —NH((C₁-C₆)alkyl) and —N((C₁-C₆)alkyl)₂;

R¹⁵ and R¹⁶ are each independently selected from the group consisting of—H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl,—(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹⁵ and R¹⁶ is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl),—(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl),—NH₂, —NH((C₁-C₆)alkyl) and —N((C₁-C₆)alkyl)₂;

wherein one or two carbon ring atoms in each of the aforementioned—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl and —(C₆-C₉)heterobicycloalkenyl in said R¹and R⁶-R¹⁴ groups may optionally and independently be replaced with—C(O)— or —C(S)—;

wherein two groups attached to the same tetravalent carbon atom in eachof the aforementioned —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₅-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl and—(C₆-C₉)heterobicycloalkenyl of said R¹ and R⁶-R¹⁴ groups may optionallyjoin to form a ring system selected from the group consisting of a—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,and —(C₄-C₉)heterocycloalkenyl; and wherein

j is an integer from 0 to 2; and

m is an integer from 0 to 3.

The present invention also provides a compound of formula Id:

or a pharmaceutically acceptable salt thereof; wherein

A is phenyl or a 5- to 6-membered heteroaryl;

B is selected from the group consisting of phenyl, pyridyl, pyrimidinyland pyrazinyl;

each R¹ is independently selected from the group consisting of —H, halo,—CF₃, —CN, —C(O)NR⁷R⁸, —C(O)R⁹, —OR¹⁰, and —(C₁-C₆)alkyl; and whereinthe —(C₁-C₆)alkyl moiety of said R¹ is optionally independentlysubstituted by one to three R¹² groups;

R² and R³ are each independently selected from the group consisting of—H and —(C₁-C₆)alkyl;

R⁴ and R⁵ are each independently selected from the group consisting of—H and —(C₁-C₆)alkyl;

R⁷ and R⁸ are each independently selected from the group consisting of—H, —OR¹⁰, —S(O)_(j)R¹¹, —NO₂, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R⁷ and R⁸ is optionally substituted by one to three R¹² groups;

each R⁹ is independently selected from the group consisting of —H,-halo, —NR¹³R¹⁴, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl,—(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, (C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R⁹ is optionally substituted by oneto three R¹² groups;

each R¹⁰ is independently selected from the group consisting of —H,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R¹⁰ is optionally substituted by one to three R¹² groups;

each R¹¹ is independently selected from the group consisting of —H,—NR¹³R¹⁴, —C(O)R¹³, —CF₃, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; land wherein each of the foregoing—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl moietiesof said R¹¹ is optionally substituted by one to three R¹² groups;

each R¹² is independently selected from the group consisting of —H,—OR¹³, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —OC(O)OR¹³, —C(O)NR¹³R¹⁴,—NR¹³C(O)NR¹³R¹⁴, —NR¹³R¹⁴, —NR¹³C(NR¹³R¹⁴)(═NR¹³),—NR¹³C(NR¹³R¹⁴)(═N—C(O)R¹³), —NR¹³C(O)R¹⁴, —NR¹³S(O)_(j)R¹³,—S(O)_(j)R¹³, —CF₃, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹² is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)R¹⁵, —C(O)NR¹⁵R¹⁶,—S(O)_(j)R¹⁵, and —S(O)_(j)NR¹⁵R¹⁶, —(C₃-C₁₀)cycloalkyl,—(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl), —NH₂, —NH((C₁-C₆)alkyl)and —N((C₁-C₆)alkyl)₂;

R¹³ and R¹⁴ are each independently selected from the group consisting of—H, —NR¹⁵C(O)R¹⁶, —CF₃, —CN, —S(O)_(j)R¹⁵, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl; and wherein each of the foregoing —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹³ and R¹⁴ is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl),—(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl),—NH₂, —NH((C₁-C₆)alkyl) and —N((C₁-C₆)alkyl)₂;

R¹⁵ and R¹⁶ are each independently selected from the group consisting of—H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₆-C₁₀)bicycloalkyl,—(C₆-C₁₀)bicycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₉)heterobicycloalkyl,—(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₆-C₁₀)bicycloalkyl, —(C₆-C₁₀)bicycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl,—(C₆-C₉)heterobicycloalkyl, —(C₆-C₉)heterobicycloalkenyl, —(C₆-C₁₀)aryl,and —(C₁-C₉)heteroaryl of said R¹⁵ and R¹⁶ is optionally independentlysubstituted by one to three groups selected from the group consisting of-halo, —CF₃, —CN, —NO₂, —OH, —O((C₁-C₆)alkyl), —C(O)((C₁-C₆)alkyl),—(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocycloalkyl, —SH, —S((C₁-C₆)alkyl),—NH₂, —NH((C₁-C₆)alkyl) and —N((C₁-C₆)alkyl)₂;

j is an integer from 0 to 2; and

m is an integer from 1 to 3.

In another embodiment, the invention relates to a compound of formula Idwherein A is a phenyl.

In another embodiment, the invention relates to a compound of formula Idwherein the moiety

represents a moiety selected from the group consisting of:

In another embodiment, the invention relates to a compound of formula Idwherein R¹ is —C(O)NR⁷R⁸ and R⁷ and R⁸ are each independently selectedfrom the group consisting —H and —(C₁-C₆)alkyl.

In another embodiment, the invention relates to a compound of formula Idwherein R¹ is —OR¹⁰ and R¹⁰ is —(C₁-C₆)alkyl.

In another embodiment, the invention relates to a compound of formula Idwherein each R¹ is independently selected from the group consisting of—H, fluoro, chloro, —CF₃, —CN, methyl, —C(O)NH₂, —C(O)NHCH₃,—C(O)NHCH₂CH₃, —C(O)N(CH₃)₂, and —OCH₃.

In another embodiment, the invention relates to a compound of formula Idwherein the moiety

represents a moiety selected from the group consisting of:

R¹ is —C(O)NH₂ or —C(O)NHCH₃; and

R^(1a) is selected from the group consisting of fluoro, chloro, methyland —OCH₃.

In another embodiment, the invention relates to a compound of formula Idwherein R² and R³ are —H.

In another embodiment, the invention relates to a compound of formula Idwherein R⁴ and R⁵ are methyl.

In another embodiment, the invention relates to a compound of formula Idwherein m is 1 or 2.

In another embodiment, the invention relates to a compound of formula Iwherein each R¹ is independently selected from the group consisting of—H, fluoro, chloro, —CF₃, —CN, —(C₁-C₆)alkyl, —C(O)NR⁷R⁸, and —OR¹⁰.

In another embodiment, the invention relates to a compound of formula Iwherein R¹ is —C(O)NR⁷R⁸ and R⁷ and R⁸ are each independently selectedfrom the group consisting —H and —(C₁-C₆)alkyl.

In another embodiment, the invention relates to a compound of formula Iwherein R², R³, R⁴ and R⁵ are each independently selected from the groupconsisting of —H and —(C₁-C₆)alkyl.

In another embodiment, the invention relates to a compound of formula Iwherein R² and R³ are —H.

In another embodiment, the invention relates to a compound of formula Iwherein R⁴ and R⁵ are methyl.

In another embodiment, the invention relates to a compound of formula Iwherein R⁶ is —CF₃, K is CH, m is 1 or 2, and n is 1.

In another embodiment, the invention relates to a compound of formula Iwherein the moiety

represents a moiety selected from the group consisting of:

In another embodiment, the invention relates to a compound of formula I,Ia, Ib, Ic or Id wherein R¹² further includes halo.

In another embodiment, the invention relates to a compound of formula I,Ia or Ib wherein R⁴ is selected from the group consisting of —H, —NR⁷R⁸,—OR¹⁰, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl;wherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R⁴ is optionally substituted by oneto three R¹² groups; and wherein R⁴ is not —H when B is a 5- to6-membered heteroaryl; and R⁵ is selected from the group consisting of—NR⁷R⁸, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl, —(C₂-C₉)heterocycloalkyl,—(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and —(C₁-C₉)heteroaryl; andwherein each of the foregoing —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₁₀)cycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₂-C₉)heterocycloalkyl, —(C₄-C₉)heterocycloalkenyl, —(C₆-C₁₀)aryl and—(C₁-C₉)heteroaryl moieties of said R⁵ is optionally substituted by oneto three R¹² groups;

In one embodiment, the invention also relates to the compounds describedas Compounds 1-415 in Examples 1-415 in the Examples section of thesubject application, and pharmaceutically acceptable salts thereof.

Non-limiting examples of compounds representing the scope of thisinvention include:

-   4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   4-({4-[({3-[methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   4-{[4-({3-[methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzamide;-   3-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   4-methoxy-3-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   N-methyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   N-methyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   3-fluoro-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   2-fluoro-4-({4-[({3-[methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   2-fluoro-4-{[4-({3-[methyl(methyl    sulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzamide;-   2-methyl-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   2-methyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   2-methyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   3-methyl-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   3-methyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   3-methyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   2-chloro-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   2-chloro-4-({4-[({3-[methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   2-chloro-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   3-fluoro-N-methyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   2-fluoro-N-methyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   N,2-dimethyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   N,3-dimethyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;    and-   N,3-dimethyl-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;    or a pharmaceutically acceptable salt thereof.

Non-limiting examples of compounds representing the scope of thisinvention also include:

-   (R)—N-(3-((2-(4-(1-aminoethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethane-sulfonamide;-   N-(3-((2-(4-(aminomethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethane-sulfonamide;-   N-[4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]acetamide;-   N-(3-((2-(4-(hydroxymethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethane-sulfonamide;-   N-(3-((2-(4-(chloromethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethane-sulfonamide;-   N-(3-((2-(4-((1,3-dihydroxypropan-2-ylamino)methyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethane-sulfonamide;-   tert-butyl    3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzoate;-   3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzoic    acid;-   N-cyclopropyl-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   N-(3-((2-(4-(1-hydroxyethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide;-   2-fluoro-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   3-fluoro-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;    and-   N-methyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;    or a pharmaceutically acceptable salt thereof.

Non-limiting examples of compounds representing the scope of thisinvention also include:

-   2-fluoro-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;-   3-fluoro-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;    and-   N-methyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide;    or a pharmaceutically acceptable salt thereof.

Non-limiting examples of compounds representing the scope of thisinvention also include:

-   2-fluoro-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide    formate;-   3-fluoro-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide    formate; and-   N-methyl-4-({4-[({3-[methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide    hydrochloride.

As used herein, the term “alkyl,” as well as the alkyl moieties of othergroups referred to herein (e.g., alkoxy), may be linear or branched(such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,secondary-butyl, tertiary-butyl); optionally substituted by 1 to 3suitable substituents as defined above such as fluoro, chloro,trifluorornethyl, —(C₁-C₆)alkoxy, —(C₆-C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy or —(C₁-C₆)alkyl. The phrase “each of said alkyl” asused herein refers to any of the preceding alkyl moieties within a groupsuch alkoxy, alkenyl or alkylamino. Preferred alkyls include(C₁-C₆)alkyl, more preferred are (C₁-C₄)alkyl, and most preferred aremethyl and ethyl.

As used herein, the term “halogen” or “halo’ includes fluoro, chloro,bromo or iodo or fluoride, chloride, bromide or iodide.

As used herein, the term “alkenyl” means straight or branched chainunsaturated radicals of 2 to 6 carbon atoms, including, but not limitedto ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, —(C₁-C₆)alkoxy, —(C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or —(C₁-C₆)alkyl.

As used herein, the term “alkynyl” means straight or branchedhydrocarbon chain radicals having one triple bond including, but notlimited to, ethynyl, propynyl, butynyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, —(C₁-C₆)alkoxy, —(C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or —(C₁-C₆)alkyl.

As used herein, the term “carbonyl” or “C(O)” (as used in phrases suchas alkylcarbonyl, alkyl-C(O)— or alkoxycarbonyl) refers to the joinderof the >C═O moiety to a second moiety such as an alkyl or amino group(i.e. an amido group). Alkoxycarbonylamino (i.e. alkoxy-C(O)—NH—) refersto an alkyl carbamate group. The carbonyl group is also equivalentlydefined herein as C(O). Alkylcarbonylamino refers to groups such asacetamide.

As used herein, the term “cycloalkyl” refers to a mono-carbocyclic ring(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl); optionally substituted by 1 to 3 suitablesubstituents as defined above such as fluoro, chloro, trifluoromethyl,—(C₁-C₆)alkoxy, —(C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or—(C₁-C₆)alkyl. Cycloalkyls include —(C₃-C₁₀)cycloalkyl.

As used herein, the term “cycloalkenyl” refers to a cycloalkyl asdefined above and further containing 1 or 2 double bonds (e.g.,cyclopentenyl, cyclohexenyl). Cycloalkenyls include—(C₅-C₁₀)cycloalkenyl.

The term “4- to 7-membered carbocyclyl” refers to a non-aromatic ringcontaining 4 to 7 carbon ring atoms, optionally containing 1 or 2 doublebonds, and optionally substituted by 1 to 3 suitable substituents asdefined above such as fluoro, chloro, trifluoromethyl, —(C₁-C₆)alkoxy,—(C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or —(C₁₋C₆)alkyl.Non-limiting examples of 4- to 7-membered carbocyclyls includecyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclopentendienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl,cycloheptyl, cycloheptenyl, and cycloheptadienyl.

As used herein, the term “bicycloalkyl” refers to a cycloalkyl asdefined above which is bridged to a second carbocyclic ring (e.g.,bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl,etc.). Bicycloalkyls include —(C₆-C₁₀)bicycloalkyl.

As used herein, the term “bicycloalkenyl” refers to a bicycloalkyl asdefined above and further containing 1 or 2 double bonds.Bicycloalkenyls include —(C₆-C₁₀)bicycloalkenyl.

As used herein, the term “(C₆-C₁₀)aryl” means aromatic radicals such asphenyl, naphthyl, tetrahydronaphthyl, indanyl and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above.

As used herein, the term “(C₁-C₉)heteroaryl” refers to an aromaticheterocyclic group having from 1 to 9 carbon atoms and containing from 1to 4 heteroatoms in the ring selected from the group consisting of O, Sand N. In addition to said heteroatom, the aromatic group may optionallyhave up to four N atoms in the ring. For example, heteroaryl groupincludes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl,imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl),thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl,triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g.,1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl,isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, —(C₁-C₆)alkoxy, —(C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or —(C₁-C₆)alkyl.

The term “5- to 6-membered heteroaryl ring” refers to an aromatic ringcontaining from 1 to 5 carbon atoms ring atoms and from 1 to 4 heteroring atoms, and optionally substituted by 1 to 3 suitable substituentsas defined above such as fluoro, chloro, trifluoromethyl,—(C₁-C₆)alkoxy, —(C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or—(C₁-C₆)alkyl. Non-limiting examples of 5- to 6-membered heteroarylrings include furanyl, pyrrolyl, thiopenyl, thiazolyl, isothiazolyl,pyrazolyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, oxadiazoyl, thiadiazoyl, benzothiazolyl, and benzooxazolyl.

As used herein, the term heteroatom refers to an atom or group selectedfrom N, O, S(O)_(q) or NR, where q is an integer from 0 to 2 and R is asubstituent group.

The term “(C₁-C₉)heterocycloalkyl” as used herein refers to a cyclicgroup containing 1 to 9 carbon atoms and 1 to 4 hetero atoms.Non-limiting examples of said monocyclic saturated or partiallysaturated ring systems are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl,pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl,piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl,piperazin-3-yl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,thiomorpholin-yl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl,1,2,5-oxathiazin-4-yl and the like; optionally containing 1 or 2 doublebonds and optionally substituted by 1 to 3 suitable substituents asdefined above such as fluoro, chloro, trifluoromethyl, —(C₁-C₆)alkoxy,—(C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or —(C₁-C₆)alkyl.

As used herein, the term “heterocycloalkenyl” refers to aheterocycloalkyl as defined above and further containing 1 or 2 doublebonds. Heterocycloalkenyls include —(C₄-C₉)heterocycloalkenyl.

The term “4- to 7-membered heterocyclyl” refers to a non-aromatic ringcontaining from 1 to 6 carbon atoms ring atoms and from 1 to 4 heteroring atoms, optionally containing 1 or 2 double bonds, and optionallysubstituted by 1 to 3 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, —(C₁-C₆)alkoxy, —(C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or —(C₁-C₆)alkyl. Non-limitingexamples of 4- to 7-membered heterocyclyls include azetidinyl, oxetanyl,pyrrolidinyl, dihydropyrazolyl, tetrahydropyrazolyl, dihydrofuranyl,tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl,dihydropyridinyl, tetrahydropyridinyl, piperidinyl, piperazinyl,pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyrianyl,dihydrothiopyranyl, tetrahydrothiopyranyl, morpholinyl, dihydroazepinyl,tetrahydroazepinyl, dihydrooxepinyl, tetrahydrooxepinyl, oxepanyl,dihyrothiepinyl, tetrahydrothiepinyl and thiepanyl.

As used herein, the term “heterobicycloalkyl” refers to a bicycloalkylas defined above, wherein at least one of the carbon ring atoms has beenreplaced by at least one heteroatom (e.g. tropane). Heterobicycloalkylsinclude —(C₆-C₉)heterobicycloalkyl.

As used herein, the term “heterobicycloalkenyl” refers to aheterobicycloalkyl as defined above and further containing 1 or 2 doublebonds. Heterobicycloalkenyls include —(C₆-C₉)heterocycloalkenyl.

Nitrogen heteroatoms as used herein refers to N═, >N and —NH; wherein—N═ refers to a nitrogen double bond; >N refers to a nitrogen containingtwo bond connections and —N refers to a nitrogen containing one bond.

The term “perfluorinated” or “perfluoro” refer to a compound having 4 ormore fluorine groups.

The term “replaced by” refers to compounds in which an element selectedfrom the group consisting of —C(O)— and —C(S)— replaces a methylenemoiety in a non-aromatic cyclic ring system. For example, if asubstituent is a heterocycloalkyl group, such as an azetidine group:

a methylene ring moiety may be replaced by, e.g., a —C(O)— to form apyrrolidinone group:

Compounds of the invention can accommodate up to three suchreplacements.

The present invention also includes isotopically-labeled compounds,which are identical to those recited in formulae I, Ia, Ib, Ic, Id andIl, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²p,³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of the present invention,prodrugs thereof, and pharmaceutically acceptable salts of saidcompounds or of said prodrugs which contain the aforementioned isotopesand/or other isotopes of other atoms are within the scope of thisinvention. Certain isotopically-labeled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically-labeled compounds of this invention andprodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily availableisotopically-labeled reagent for a non-isotopically-labeled reagent.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups which maybe present in the compounds of the present invention. The compounds ofthe present invention that are basic in nature are capable of forming awide variety of salts with various inorganic and organic acids. Theacids that may be used to prepare pharmaceutically acceptable acidaddition salts of such basic compounds are those that form non-toxicacid addition salts, i.e., salts containing pharmacologically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,bitartrate, ascorbate, succinate, rnaleate, gentisinate, furrarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.The compounds of the present invention that include a basic moiety, suchas an amino group, may form pharmaceutically acceptable salts withvarious amino acids, in addition to the acids mentioned above.

The invention also relates to base addition salts of the compounds ofthe invention. The chemical bases that may be used as reagents toprepare pharmaceutically acceptable base salts of those compounds of thecompounds of the invention that are acidic in nature are those that formnon-toxic base salts with such compounds. Such non-toxic base saltsinclude, but are not limited to those derived from suchpharmacologically acceptable cations such as alkali metal cations (e.g.,potassium and sodium) and alkaline earth metal cations (e.g., calciumand magnesium), ammonium or water-soluble amine addition salts such asN-methylglucamine-(meglumine), and the lower alkanolammonium and otherbase salts of pharmaceutically acceptable organic amines.

Suitable base salts are formed from bases which form non-toxic salts.Non-limiting examples of suitable base salts include the aluminum,arginine, benzathine, calcium, choline, diethylamine, diolamine,glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example,hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).Methods for making pharmaceutically acceptable salts of compounds of theinvention are known to one of skill in the art.

This invention also encompasses compounds of the invention containingprotective groups. One skilled in the art will also appreciate thatcompounds of the invention can also be prepared with certain protectinggroups that are useful for purification or storage and can be removedbefore administration to a patient. The protection and deprotection offunctional groups is described in “Protective Groups in OrganicChemistry”, edited by J. W. F. McOmie, Plenum Press (1973) and“Protective Groups in Organic Synthesis”, 3rd edition, T. W. Greene andP. G. M. Wuts, Wiley-Interscience (1999).

The compounds of this invention include all stereoisomers (e.g., cis andtrans isomers) and all optical isomers of compounds of the invention(e.g., R and S enantiomers), as well as racemic, diastereomeric andother mixtures of such isomers.

The compounds, salts and prodrugs of the present invention can exist inseveral tautomeric forms, including the enol and imine form, and theketo and enamine form and geometric isomers and mixtures thereof. Allsuch tautomeric forms are included within the scope of the presentinvention. Tautomers exist as mixtures of a tautomeric set in solution.In solid form, usually one tautomer predominates. Even though onetautomer may be described, the present invention includes all tautomersof the present compounds.

The present invention also includes atropisomers of the presentinvention. Atropisomers refer to compounds of the invention that can beseparated into rotationally restricted isomers.

The compounds of this invention may contain olefin-like double bonds.When such bonds are present, the compounds of the invention exist as cisand trans configurations and as mixtures thereof.

The compounds of the invention may also exist in unsolvated and solvatedforms. Accordingly, the invention also relates to the hydrates andsolvates of the compounds of the invention. Thus, it will be understoodthat the compounds of formula I, and pharmaceutically acceptable saltsthereof also include hydrates and solvates of said compounds of formulaI, and pharmaceutically acceptable salts thereof, as discussed below.

The term “solvate” is used herein to describe a noncovelent or easilyreversible combination between solvent and solute, or dispersion meansand disperse phase. It will be understood that the solvate can be in theform of a solid, slurry (e.g., a suspension or dispersoid), or solution.Non-limiting examples of solvents include ethanol, methanol, propanol,acetonitrile, dimethyl ether, diethyl ether, tetrahydrofuan, methylenechloride, and water. The term ‘hydrate’ is employed when said solvent iswater.

A currently accepted classification system for organic hydrates is onethat defines isolated site, channel, or metal-ion coordinatedhydrates—see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed.H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones inwhich the water molecules are isolated from direct contact with eachother by intervening organic molecules. In channel hydrates, the watermolecules lie in lattice channels where they are next to other watermolecules. In metal-ion coordinated hydrates, the water molecules arebonded to the metal ion.

When the solvent or water is tightly bound, the complex will have awell-defined stoichiometry independent of humidity. When, however, thesolvent or water is weakly bound, as in channel solvates and hygroscopiccompounds, the water/solvent content will be dependent on humidity anddrying conditions. In such cases, non-stoichiometry will be the norm.

The invention also relates to prodrugs of the compounds of theinvention. Thus certain derivatives of compounds of the invention whichmay have little or no pharmacological activity themselves can, whenadministered into or onto the body, be converted into compounds of theinvention having the desired activity, for example, by hydrolyticcleavage. Such derivatives are referred to as “prodrugs”. Furtherinformation on the use of prodrugs may be found in Pro-drugs as NovelDelivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W.Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987(Ed. E. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds of theinvention with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in Design of Prodrugs by H.Bundgaard (Elsevier, 1985).

Some non-limiting examples of prodrugs in accordance with the inventioninclude

(i) where the compound of the invention contains a carboxylic acidfunctionality (—COOH), an ester thereof, for example, a compound whereinthe hydrogen of the carboxylic acid functionality of the compound offormula (I) is replaced by (C₁-C₆)alkyl;

(ii) where the compound of the invention contains an alcoholfunctionality (—OH), an ether thereof, for example, a compound whereinthe hydrogen of the alcohol functionality of the compound of theinvention is replaced by (C₁-C₆)alkanoyloxymethyl; and

(iii) where the compound of the invention contains a primary orsecondary amino functionality (—NH₂ or —NHR where R≠H), an amidethereof, for example, a compound wherein, as the case may be, one orboth hydrogen atoms of the amino functionality of the compound of theinvention is/are replaced by (C₁-C₆)alkanoyl.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

Moreover, certain compounds of the invention may themselves act asprodrugs of other compounds of the invention.

Also included within the scope of the invention are metabolites ofcompounds of the invention, that is, compounds formed in vivo uponadministration of the drug. Some examples of metabolites in accordancewith the invention include:

(i) where the compound of the invention contains a methyl group, anhydroxymethyl derivative thereof (e.g., —CH₃->—CH₂OH):

(ii) where the compound of the invention contains an alkoxy group, anhydroxy derivative thereof (e.g., —OR⁷->—OH);

(iii) where the compound of the invention contains a tertiary aminogroup, a secondary amino derivative thereof (e.g., —NR³R⁴->—NHR³ or—NHR⁴);

(iv) where the compound of the invention contains a secondary aminogroup, a primary derivative thereof (e.g., —NHR³->—NH₂);

(v) where the compound of the invention contains a phenyl moiety, aphenol derivative thereof (e.g., -Ph ->-PhOH); and

(vi) where the compound of the invention contains an amide group, acarboxylic acid derivative thereof (e.g., —CONH₂->COOH).

Compounds of the invention containing one or more asymmetric carbonatoms can exist as two or more stereoisomers. Where a compound of theinvention contains an alkenyl or alkenylene group, geometric cis/trans(or Z/E) isomers are possible. Where structural isomers areinterconvertible via a low energy barrier, tautomeric isomerism(‘tautomerism’) can occur. This can take the form of proton tautomerismin compounds of the invention containing, for example, an imino, keto,or oxime group, or so-called valence tautomerism in compounds whichcontain an aromatic moiety. It follows that a single compound mayexhibit more than one type of isomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof the invention, including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counterion is optically active, forexample, d-lactate or l-lysine, or racemic, for example, dl-tartrate ordl-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallization.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of the invention contains an acidic or basicmoiety, a base or acid such as 1-phenylethylamine or tartaric acid. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50% byvolume of an alcoholic solvent such as isopropanol, typically from 2% to20%, and from 0 to 5% by volume of an alkylamine, typically 0.1%diethylamine. Concentration of the eluate affords the enriched mixture.

When any racemate crystallizes, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture haveidentical physical properties, they may have different physicalproperties compared to the true racemate. Racemic mixtures may beseparated by conventional techniques known to those skilled in theart—see, for example, Stereochemistry of Organic Compounds by E. L.Eliel and S. H. Wilen (Wiley, 1994).

In one embodiment, the invention relates to compositions comprising acompound of the invention and at least one additional ingredient(hereinafter “the compositions of the invention”). It will be understoodthat the compositions of the invention will encompass any combination ofthe compound of the invention and the at least one additionalingredient. Non-limiting examples of the at least one additionalingredient include impurities (e.g., intermediates present in theunrefined compounds of the invention), active ingredients as discussedherein (e.g., an additional anti-tumor agent), pharmaceuticallyacceptable excipients, or one or more solvents (e.g., a pharmaceuticallyacceptable carrier as discussed herein).

The term “solvent” as it relates to the compositions of the inventionincludes organic solvents (e.g., methanol, ethanol, isopropanol, ethylacetate, methylene chloride, and tetrahydrofuran) and water. The one ormore solvents may be present in a non-stoichiometric amount, e.g., as atrace impurity, or in sufficient excess to dissolve the compound of theinvention. Alternatively, the one or more solvents may be present in astoichiometric amount, e.g., 0.5:1, 1:1, or 2:1 molar ratio, based onthe amount of compound of the invention.

In one embodiment, the at least one additional ingredient that ispresent in the composition of the invention is an organic solvent.

In another embodiment, the at least one additional ingredient that ispresent in the composition of the invention is water.

In one embodiment, the at least one additional ingredient that ispresent in the composition of the invention is a pharmaceuticallyacceptable carrier.

In another embodiment, the at least one additional ingredient that ispresent in the composition of the invention is a pharmaceuticallyacceptable excipient.

In one embodiment, the composition of the invention is a solution.

In another embodiment, the composition of the invention is a suspension.

In another embodiment, the composition of the invention is a solid.

In another embodiment, the composition of the invention comprises anamount of the compound of the invention effective for treating abnormalcell growth.

In yet another embodiment, the invention relates to a compositioncomprising an effective amount of the compound of the invention, and apharmaceutically acceptable carrier.

In another embodiment, the invention relates to a composition comprisinga therapeutically effective amount of the compound the invention asdefined above, a pharmaceutically acceptable carrier and, optionally, atleast one additional medicinal or pharmaceutical agents (hereinafter“the pharmaceutical compositions of the invention”). In a preferredembodiment, the at least one additional medicinal or pharmaceuticalagent is an anti-cancer agent.

In another embodiment, the invention relates to a composition useful fortreating abnormal cell growth in a mammal comprising an effective amountof the compound of the invention, and a pharmaceutically acceptablecarrier.

The invention also relates to methods of making the compounds of theinvention.

In one embodiment, the invention relates to a method for making acompound of formula I comprising allowing a compound of formula

to react with a compound of formula

to provide the compound of formula I.

In another embodiment, the invention relates to a method for making thecompounds of the invention comprising allowing a compound of formula

to react with a compound of formula

When preparing compounds of the invention in accordance with theinvention, it is open to a person skilled in the art to routinely selectthe form of the intermediate compound which provides the bestcombination of features for this purpose. Such features include themelting point, solubility, processability and yield of the intermediateform and the resulting ease with which the product may be purified onisolation.

The invention also relates to intermediate compounds that are useful formaking the compounds of the invention.

In one embodiment, the invention relates to intermediate compoundshaving the formula II:

wherein A, K, R¹, R⁶ and m are as defined above for the compound offormula I.

The invention also relates to methods for the treatment of abnormal cellgrowth in a mammal. In one embodiment, the invention relates to a methodfor the treatment of abnormal cell growth in a mammal comprisingadministering to said mammal an amount of a compound of the inventionthat is effective in treating abnormal cell growth.

In another embodiment, the abnormal cell growth is cancer.

In another embodiment, the cancer is selected from the group consistingof lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer ofthe head or neck, cutaneous or intraocular melanoma, uterine cancer,ovarian cancer, rectal cancer, cancer of the anal region, stomachcancer, colon cancer, breast cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system, cancer of the thyroid gland, cancer of the parathyroidgland, cancer of the adrenal gland, sarcoma of soft tissue, cancer ofthe urethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers.

The invention also relates to methods for the treatment of cancer solidtumors in a mammal. In one embodiment, the invention relates to thetreatment of cancer solid tumor in a mammal comprising administering tosaid mammal an amount of a compound of the invention that is effectivein treating said cancer solid tumor.

In another embodiment, the cancer solid tumor is breast, lung, colon,brain, prostate, stomach, pancreatic, ovarian, skin (melanoma),endocrine, uterine, testicular, or bladder.

In another embodiment, the invention relates to a method for thetreatment of abnormal cell growth in a mammal which comprisesadministering to said mammal an amount of a compound of the inventionthat is effective in treating abnormal cell growth in combination withan anti-tumor agent selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, radiation, cell cycle inhibitors,enzymes, topoisomerase inhibitors, biological response modifiers,antibodies, cytotoxics, anti-hormones, and anti-androgens.

A particular aspect of this invention is directed to methods fortreating or preventing a condition that presents with low bone mass in amammal (including a human being) which comprise administering to amammal in need of such treatment a condition that presents with low bonemass treating amount of a compound of the invention or apharmaceutically acceptable salt of said compound of the invention. Thisinvention is particularly directed to such methods wherein the conditionthat presents with low bone mass is osteoporosis, frailty, anosteoporotic fracture, a bone defect, childhood idiopathic bone loss,alveolar bone loss, mandibular bone loss, bone fracture, osteotomy,periodontitis or prosthetic ingrowth.

A particular aspect of this invention is directed to methods fortreating osteoporosis in a mammal (including a human being) whichcomprise administering to a mammal in need of such treatment anosteoporosis treating amount of a compound of the invention or apharmaceutically acceptable salt of said compound.

Another aspect of this invention is directed to methods for treating abone fracture or an osteoporotic fracture in a mammal which compriseadministering to a mammal in need of such treatment a bone fracturetreating or an osteoporotic fracture treating amount of a compound ofthe invention or a pharmaceutically acceptable salt of said compound.

The term “osteoporosis” includes primary osteoporosis, such as senile,postmenopausal and juvenile osteoporosis, as well as secondaryosteoporosis, such as osteoporosis due to hyperthyroidism or Cushingsyndrome (due to corticosteroid use), acromegaly, hypogonadism,dysosteogenesis and hypophospatasemia.

DETAILED DESCRIPTION OF THE INVENTION Synthesis of 2,4-DiaminoPyrimidines

The compounds of the invention can be prepared by the following generalmethods and by methods described in detail in the Experimental Section.

Non-limiting methods for making the sulfonyl amides of the invention aredepicted in Schemes 1-6 below. For sake of clarity, only the pyrimidinederivatives of the compounds of formula I are depicted in the Schemes(i.e., where K of the compound of formula I is CH). However, the samemethods can be used for making the 1,2,4-triazine derivatives compoundsof formula I (i.e., where K is N).

Scheme 1 shows one method for preparing 2,4-diamino pyrimidines.

In Scheme 1, the amino group of an amino-nitroaryl compound of structureA1-1 is protected (PG=protecting group such as BOC) to form theprotected compound A1-2. The nitro group of A1-2 can then be selectivelyreduced to the corresponding aniline A1-3, using, e.g., hydrogen in thepresence of a palladium-supported catalyst. Reaction of aniline A1-3with 2,4-dichloro-5-(trifluoromethyl)pyrimidine in the presence of anappropriate zinc salt (e.g., ZnBr₂) provides the corresponding C-2addition product A1-4. Reaction of compounds of formula A1-4 with aminesof formula A1-7 under basic conditions provides compound of formula Ihaving the structure A1-5. Other compounds of formula I can be preparedby selectively deprotecting A1-5 to provide the aminoalkyl compound offormula I having the structure A1-6.

Scheme 2 depicts a non-limiting method for making amide derivatives ofthe compound of formula I.

In Scheme 2, an aminoalkyl such as the compound of formula I having thestructure A1-6 can be reacted with an acid halide (e.g., acetylchloride) under basic conditions to provide the amide derivative of thecompound of formula I having the structure A2-1.

Scheme 3 represents another general non-limiting method of makingcompounds of formula I.

In Scheme 3, an hydroxyalkyl-aniline of formula A3-1 is reacted with2,4-dichloro-5-(trifluoromethyl) pyrimidine in the presence of a zincsalt (e.g., ZnBr₂) to provide the corresponding C-2 addition productA3-2. Treatment of the A3-2 with an amine of formula A3-6 provideshydroxyalkyl derivatives of the compound of formula I having thestructure A3-3. Compound A3-3 may further be selectively converted to acompound of formula I where the hydroxyl group is replaced for anotherreactive functional group (e.g., alkyl halide or alkyl sulfonate). Forexample, in Scheme 3, the hydroxylalkyl compound of formula A3-3 isreacted with thionyl chloride to provide the chloroalkyl compound offormula I having the structure A3-4. Compound A3-4 may further bereacted with amines (e.g., HNR⁷R⁸) to provide aminoalkyl derivatives ofthe compounds of formula I having the structure A3-5. If desired, thecompounds of structure A3-5 can be used as a starting material toprepare other compounds of formula I.

Scheme 4 represents yet another general non-limiting method for makingcompounds of formula I.

In Scheme 4, the acid group of a nitrobenzoate compound of structureA4-1 is protected to form the protected compound A4-2. The nitro groupof A4-2 can then be selectively reduced to the corresponding anilineA4-3, using, e.g., hydrogen in the presence of a palladium-supportedcatalyst. Reaction of aniline A4-3 with2,4-dichloro-5-(trifluoromethyl)pyrimidine in the presence of anappropriate zinc salt (e.g., ZnBr₂) provides the corresponding C-2addition product A4-4. Treatment of the chloro-pyrimidine compounds offormula A4-4 with amines of formula A4-7 provides benzoate-protectedcompounds of formula I having the structure A4-5. Selective deprotectionof compound A4-5 can provide benzoic acid derivatives of the compound offormula I having the structure A4-6. The benzoic acid derivatives offormula A4-6 may be further reacted with an amine to provide the amidederivatives of the compound of formula I having the structure A4-6.

Scheme 5 depicts yet another general non-limiting method for makingcompounds of formula I.

In Scheme 5, an aniline amide compound of structure A5-1 is be reactedwith 2,4-dichloro-5-(trifluoromethyl)pyrimidine in the presence of azinc salt (e.g., ZnBr₂) to provide the corresponding C-2 additionproduct A5-2. Treatment of the chloro pyrimidine compounds of formulaA5-2 with an amine of formula A5-3 provides amide derivatives of thecompounds of formula I having the structure A5-4. The amide derivativesof formula A5-4 may be used as a starting material to provide othercompounds of formula I.

In Schemes 1 and 3-5, the 2,4-dichloro-5-(trifluoromethyl)pyrimidinefirst formed a C-2 addition product (“the C4-chloro intermediate”). TheC-4 group was then added by allowing the C4-chloro intermediate to reactwith an aralkylamino reagent. Scheme 6 depicts another non-limitingmethod for making the compounds of the invention where the first formedintermediate is the C-4 addition intermediate (“the C2-chlorointermediate”).

In Scheme 6, 2,4-dichloro-5-(trifluoromethyl)pyrimidine is reacted withan aralkylamino reagent of formula A6-2 to provide the2-chloro-pyrimidine addition product A6-3. Reaction of A6-3 with anamino reagent of formula A6-4 provides the compound of formula I havingthe structure A6-5. Depending on the substituent groups R¹, thecompounds of formula A6-5 can be further reacted as described above inSchemes 1-5 to provide additional compounds of formula I.

Arylalkylamines or heteroarylalkylamines (e.g., A1-7 in Scheme 1) thatare attached to the 4 position of the pyrimidine core (or the 5 positionof the 1,2,4-triazine core) may be prepared from the correspondingnitrile by catalytic hydrogenation using catalysts such as Pd/C or RaneyNickel or by lithium aluminum hydride reduction, (see Rylander,Catalytic Hydrogenation in Organic Synthesis, Academic Press, 1979); orby methods described herein in the Examples section.

The nitrile starting materials can be either purchased or prepared fromthe corresponding aryl/heteroaryl bromide, iodide or triflate andZn(CN)₂ using Pd coupling conditions found in Tschaen, D. M., et. alSynthetic Communications (1994), 24, 6, pp 887-890.

Appropriately protected amines may be converted to different amines offormula A1-7 (see Scheme 1) according to methods familiar to thoseskilled in the art as, for example, N-alkylation of a sulfanilide underphase transfer using conditions as described by Brehme, R. “Synthesis”,(1976), pp 113-114.

As understood by those skilled in the art, the chemical transformationto convert an aryl halide or triflate or heteroaryl halide or triflateto an aromatic or heteroaromatic amine may be carried out usingconditions currently outlined in the literature, see Hartwig, J. F.:“Angew. Chem. Int. Ed.” (1998), 37, pp. 2046-2067, Wolfe, J. P.; Wagaw,S.; Marcoux, J. F.; Buchwald, S. L.; “Acc. Chem. Res.”, (1998), 31, pp805-818, Wolfe, J. P.; Buchwald, S. L.; “J. Org. Chem.”, (2000), 65, pp1144-1157, Muci, A. R.; Buchwald, S. L.; “Topics in Current Chemistry”(2002), pp 131-209 and references cited therein. Further, as understoodby those skilled in the art, these same aryl or heteroaryl aminationchemical transformations may alternatively be carried out on nitrile (orprimary amide) precursors which provide amines after nitrile (or amide)reduction.

Other methods for making the intermediate compounds (e.g. A1-7 inScheme 1) can be found in U.S. Patent Appl. Publ. No. 20040220177, U.S.Pat. Nos. 7,109,335, 7,109,337, and PCT/IB2006/003349, the entirecontents of each of the foregoing references being expresslyincorporated herein by reference.

As noted above, amines comprising the ring moiety A (e.g., A6-4 inScheme 6) are attached to the 2 position of the pyrimidine core (or the3 position of the 1,2,4-triazine core). Such amino-ring groups arecommercially available or can be made by methods known to those skill inthe art. For example, amines comprising alkyl-, hydroxyl-, carboxyl-,and halo-substituted ring moieties are commercially available. Inaddition, certain of these commercially available amines such as, e.g.,the halo- and hydroxyl-substituted ring compounds, can be reacted toform other compounds of the invention using the methods described above,in the Examples section, or known to those skilled in the art. Suchreactions can be carried out prior to the reaction with pyrimidine core.Alternatively, such reactions can be carried out after the cyclic amineis attached to the C2 position of the pyrimidine core.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of the invention, as defined above,or a pharmaceutically acceptable salt, solvate or prodrug thereof, thatis effective in treating abnormal cell growth. In one embodiment of thismethod, the abnormal cell growth is cancer, including, but not limitedto, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer ofthe head or neck, cutaneous or intraocular melanoma, uterine cancer,ovarian cancer, rectal cancer, cancer of the anal region, stomachcancer, colon cancer, breast cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system, cancer of the thyroid gland, cancer of the parathyroidgland, cancer of the adrenal gland, sarcoma of soft tissue, cancer ofthe urethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In one embodimentthe method comprises comprising administering to a mammal an amount of acompound of the invention that is effective in treating said cancersolid tumor. In one preferred embodiment the solid tumor is breast,lung, colon, brain, prostate, stomach, pancreatic, ovarian, skin(melanoma), endocrine, uterine, testicular, and bladder cancer.

In another embodiment of said method, said abnormal cell growth is abenign proliferative disease, including, but not limited to, psoriasis,benign prostatic hypertrophy or restinosis.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal anamount of a compound of the invention, or a pharmaceutically acceptablesalt, solvate or prodrug thereof, that is effective in treating abnormalcell growth in combination with an anti-tumor agent selected from thegroup consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens.

This invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the invention, as defined above,or a pharmaceutically acceptable salt, solvate or prodrug thereof, thatis effective in treating abnormal cell growth, and a pharmaceuticallyacceptable carrier. In one embodiment of said composition, said abnormalcell growth is cancer, including, but not limited to, lung cancer, bonecancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lyrnphorna,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In anotherembodiment of said pharmaceutical composition, said abnormal cell growthis a benign proliferative disease, including, but not limited to,psoriasis, benign prostatic hypertrophy or restinosis.

The invention also contemplates a pharmaceutical composition fortreating abnormal cell growth wherein the composition includes acompound of the invention, as defined above, or a pharmaceuticallyacceptable salt, solvate or prodrug thereof, that is effective intreating abnormal cell growth, and another anti-tumor agent selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens.

This invention also relates to a method for the treatment of a disorderassociated with angiogenesis in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the invention,as defined above, or a pharmaceutically acceptable salt, solvate orprodrug thereof, that is effective in treating said disorder incombination with one or more anti-tumor agents listed above. Suchdisorders include cancerous tumors such as melanoma; ocular disorderssuch as age-related macular degeneration, presumed ocular histoplasmosissyndrome, and retinal neovascularization from proliferative diabeticretinopathy; rheumatoid arthritis; bone loss disorders such asosteoporosis, Paget's disease, humoral hypercalcemia of malignancy,hypercalcemia from tumors metastatic to bone, and osteoporosis inducedby glucocorticoid treatment; coronary restenosis; and certain microbialinfections including those associated with microbial pathogens selectedfrom adenovirus, hantaviruses, Borrelia burgdorferi, Yersinia spp.,Bordetella pertussis, and group A Streptococcus.

This invention also relates to a method of (and to a composition for)treating abnormal cell growth in a mammal which comprise an amount of acompound of the invention, or a pharmaceutically acceptable salt,solvate or prodrug thereof, in combination with an amount of one or moresubstances selected from anti-angiogenesis agents, signal transductioninhibitors, and antiproliferative agents, which amounts are togethereffective in treating said abnormal cell growth.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II(cyclooxygenase II) inhibitors, can be used in conjunction with acompound of the invention in the methods and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(celecoxib), Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), andArcoxia (etoricoxib). Examples of useful matrix metalloproteinaseinhibitors are described in WO 96/33172 (published Oct. 24, 1996), WO96/27583 (published Mar. 7, 1996), European Patent Publication No.EP0818442, European Patent Publication No. EP1004578, WO 98/07697(published Feb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO98/34918 (published Aug. 13, 1998), WO 98/34915 (published Aug. 13,1998), WO 98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul.16, 1998), European Patent Publication 606,046 (published Jul. 13,1994), European Patent Publication 931,788 (published Jul. 28, 1999), WO90/05719 (published May 331, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Publication No. WO99/007675, EuropeanPatent Application No. 99302232.1 (filed Mar. 25, 1999), Great Britainpatent application number 9912961.1 (filed Jun. 3, 1999), U.S. Pat. Nos.7,030,242, 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510(issued Jan. 19, 1999), and European Patent Publication 780,386(published Jun. 25, 1997), all of which are herein incorporated byreference in their entirety. Preferred MMP-2 and MMP-9 inhibitors arethose that have little or no activity inhibiting MMP-1. More preferred,are those that selectively inhibit MMP-2 and/or MMP-9 relative to theother matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in combination with thecompounds of the present invention are AG-3340, RO 32-3555, RS 13-0830,and the compounds recited in the following list:

-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionic    acid;-   3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide;-   (2R, 3R)    1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic    acid hydroxyamide;-   4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic    acid hydroxyamide;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionic    acid;-   4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic    acid hydroxyamide;-   3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic    acid hydroxyamide;-   (2R, 3R)    1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic    acid hydroxyamide;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionic    acid;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetra    hydro-pyran-4-yl)-amino]-propionic acid;-   3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide;-   3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide; and-   3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic    acid hydroxyamide;

and pharmaceutically acceptable salts, solvates and prodrugs of saidcompounds.

VEGF inhibitors, for example, SU-11248, SU-5416 and SU-6668 (Sugen Inc.of South San Francisco, Calif., USA), can also be combined with acompound of the invention. VEGF inhibitors are described in, for examplein WO 99/24440 (published May 20, 1999), PCT International ApplicationPCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug. 17,1995), WO 99/61422 (published Dec. 2, 1999), U.S. Pat. No. 5,834,504(issued Nov. 10, 1998), WO 98/50356 (published Nov. 12, 1998), U.S. Pat.No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat. No. 5,886,020 (issuedMar. 23, 1999), U.S. Pat. No. 5,792,783 (issued Aug. 11, 1998), U.S.Pat. No. 6,653,308 (issued Nov. 25, 2003), WO 99/10349 (published Mar.4, 1999), WO 97/32856 (published Sep. 12, 1997), WO 97/22596 (publishedJun. 26, 1997), WO 98/54093 (published Dec. 3, 1998), WO 98/02438(published Jan. 22, 1998), WO 99/16755 (published Apr. 8, 1999), and WO98/02437 (published Jan. 22, 1998), all of which are herein incorporatedby reference in their entirety. Other examples of some specific VEGFinhibitors are IM862 (Cytran Inc. of Kirkland, Wash., USA); Avastin, ananti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco,Calif.; and angiozyme, a synthetic ribozyme from Ribozyme (Boulder,Colo.) and Chiron (Emeryville, Calif.).

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc), andthe monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of TheWoodlands, Tex., USA) and 2B-1 (Chiron), may be administered incombination with a compound of the invention. Such erbB2 inhibitorsinclude Herceptin, 2C4, and pertuzumab. Such erbB2 inhibitors includethose described in WO 98/02434 (published Jan. 22, 1998), WO 99/35146(published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17,1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No. 5,587,458(issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2,1999), each of which is herein incorporated by reference in itsentirety. ErbB2 receptor inhibitors useful in the present invention arealso described in U.S. Pat. No. 6,465,449, and in U.S. Pat. No.6,284,764, both of which are herein incorporated by reference in theirentirety. Other erbb2 receptor inhibitors include TAK-165 (Takeda) andGW-572016 (Glaxo-Wellcome).

Various other compounds, such as styrene derivatives, have also beenshown to possess tyrosine kinase inhibitory properties, and some oftyrosine kinase inhibitors have been identified as erbB2 receptorinhibitors. More recently, five European patent publications, namely EP0 566 226 A1 (published Oct. 20, 1993), EP 0 602 851 A1 (published Jun.22, 1994), EP 0 635 507 A1 (published Jan. 25, 1995), EP 0 635 498 A1(published Jan. 25, 1995), and EP 0 520 722 A1 (published Dec. 30,1992), refer to certain bicyclic derivatives, in particular quinazolinederivatives, as possessing anti-cancer properties that result from theirtyrosine kinase inhibitory properties. Also, World Patent Application WO92/20642 (published Nov. 26, 1992), refers to certain bis-mono andbicyclic aryl and heteroaryl compounds as tyrosine kinase inhibitorsthat are useful in inhibiting abnormal cell proliferation. World PatentApplications WO96/16960 (published Jun. 6, 1996), WO 96/09294 (publishedMar. 6, 1996), WO 97/30034 (published Aug. 21, 1997), WO 98/02434(published Jan. 22, 1998), WO 98/02437 (published Jan. 22, 1998), and WO98/02438 (published Jan. 22, 1998), also refer to substituted bicyclicheteroaromatic derivatives as tyrosine kinase inhibitors that are usefulfor the same purpose. Other patent applications that refer toanti-cancer compounds are World Patent Application WO00/44728 (publishedAug. 3, 2000), EP 1029853A1 (published Aug. 23, 2000), and WO01/98277(published Dec. 12, 2001) all of which are incorporated herein byreference in their entirety.

Other antiproliferative agents that may be used with the compounds ofthe present invention include inhibitors of the enzyme farnesyl proteintransferase and inhibitors of the receptor tyrosine kinase PDGFr,including the compounds disclosed and claimed in the following U.S.patent application Ser. No. 09/221,946 (filed Dec. 28, 1998); Ser. No.09/454,058 (filed Dec. 2, 1999); Ser. No. 09/501,163 (filed Feb. 9,2000); Ser. No. 09/539,930 (filed Mar. 31, 2000); Ser. No. 09/202,796(filed May 22, 1997); Ser. No. 09/384,339 (filed Aug. 26, 1999); andSer. No. 09/383,755 (filed Aug. 26, 1999); and the compounds disclosedand claimed in the following U.S. provisional patent applications:60/168,207 (filed Nov. 30, 1999); 60/170,119 (filed Dec. 10, 1999);60/177,718 (filed Jan. 21, 2000); 60/168,217 (filed Nov. 30, 1999), and60/200,834 (filed May 1, 2000). Each of the foregoing patentapplications and provisional patent applications is herein incorporatedby reference in their entirety.

A compound of the invention may also be used with other agents useful intreating abnormal cell growth or cancer, including, but not limited to,agents capable of enhancing antitumor immune responses, such as CTLA4(cytotoxic lymphocyte antigen 4) antibodies, and other agents capable ofblocking CTLA4; and anti-proliferative agents such as other farnesylprotein transferase inhibitors, for example the farnesyl proteintransferase inhibitors described in the references cited in the“Background” section, supra. Specific CTLA4 antibodies that can be usedin the present invention include those described in U.S. ProvisionalApplication 60/113,647 (filed Dec. 23, 1998) which is hereinincorporated by reference in its entirety.

A compound of formula I may be applied as a sole therapy or may involveone or more other anti-tumor substances, for example those selectedfrom, for example, mitotic inhibitors, for example vinblastine;alkylating agents, for example cis-platin, oxaliplatin, carboplatin andcyclophosphamide; anti-metabolites, for example 5-fluorouracil,capecitabine, cytosine arabinoside and hydroxyurea, or, for example, oneof the preferred anti-metabolites disclosed in European PatentApplication No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid; growth factorinhibitors; cell cycle inhibitors; intercalating antibiotics, forexample adriamycin and bleomycin; enzymes, for example interferon; andanti-hormones, for example anti-estrogens such as Nolvadex (tamoxifen)or, for example anti-androgens such as Casodex(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).

The compounds of the present invention may be used alone or incombination with one or more of a variety of anti-cancer agents orsupportive care agents. For example, the compounds of the presentinvention may be used with cytotoxic agents, e.g., one or more selectedfrom the group consisting of a camptothecin, irinotecan HCl (Camptosar),edotecarin, SU-11248, epirubicin (Ellence), docetaxel (Taxotere),paclitaxel, rituximab (Rituxan) bevacizumab (Avastin), imatinib mesylate(Gleevac), Erbitux, gefitinib (Iressa), and comrnbinations thereof. Theinvention also contemplates the use of the compounds of the presentinvention together with hormonal therapy, e.g., exemestane (Aromasin),Lupron, anastrozole (Arimidex), tamoxifen citrate (Nolvadex), Trelstar,and combinations thereof. Further, the invention provides a compound ofthe present invention alone or in combination with one or moresupportive care products, e.g., a product selected from the groupconsisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin,Procrit, Aloxi, Emend, or combinations thereof. Such conjoint treatmentmay be achieved by way of the simultaneous, sequential or separatedosing of the individual components of the treatment.

The compounds of the invention may be used with antitumor agents,alkylating agents, antimetabolites, antibiotics, plant-derived antitumoragents, camptothecin derivatives, tyrosine kinase inhibitors,antibodies, interferons, and/or biological response modifiers. In thisregard, the following is a non-limiting list of examples of secondaryagents that may be used with the compounds of the invention.

-   -   Alkylating agents include, but are not limited to, nitrogen        mustard N-oxide, cyclophosphamide, ifosfamide, melphalan,        busulfan, mitobronitol, carboquone, thiotepa, ranimustine,        nimustine, temozolomide, AMD-473, altretamine, AP-5280,        apaziquone, brostallicin, bendamustine, carmustine,        estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170,        mafosfamide, and mitolactol; platinum-coordinated alkylating        compounds include but are not limited to, cisplatin,        carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin or        satrplatin;    -   Antimetabolites include but are not limited to, methotrexate,        6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU)        alone or in combination with leucovorin, tegafur, UFT,        doxifluridine, carmofur, cytarabine, cytarabine ocfosfate,        enocitabine, S-1, gemcitabine, fludarabin, 5-azacitidine,        capecitabine, cladribine, clofarabine, decitabine, eflornithine,        ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1,        melphalan, nelarabine, nolatrexed, ocfosfate, disodium        premetrexed, pentostatin, pelitrexol, raltitrexed, triapine,        trimetrexate, vidarabine, vincristine, vinorelbine; or for        example, one of the preferred anti-metabolites disclosed in        European Patent Application No. 239362 such as        N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic        acid;    -   Antibiotics include but are not limited to: aclarubicin,        actinomycin D, amrubicin, annamycin, bleomycin, daunorubicin,        doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin,        mitomycin C, nemorubicin, neocarzinostatin, peplomycin,        pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin        or zinostatin;    -   Hormonal therapy agents, e.g., exemestane (Aromasin), Lupron,        anastrozole (Arimidex), doxercalciferol, fadrozole, formestane,        anti-estrogens such as tamoxifen citrate (Nolvadex) and        fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene,        letrozole (Femara), or anti-androgens such as bicalutamide,        flutamide, mifepristone, nilutamide, Casodex®        (4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide)        and combinations thereof;    -   Plant derived anti-tumor substances include for example those        selected from mitotic inhibitors, for example vinblastine,        docetaxel (Taxotere) and paclitaxel;    -   Cytotoxic topoisomerase inhibiting agents include one or more        agents selected from the group consisting of aclarubicin,        amonafide, belotecan, camptothecin, 10-hydroxycamptothecin,        9-aminocamptothecin, diflomotecan, irinotecan HCl (Camptosar),        edotecarin, epirubicin (Ellence), etoposide, exatecan,        gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone,        rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan, and        combinations thereof;    -   Immunologicals include interferons and numerous other immune        enhancing agents. Interferons include interferon alpha,        interferon alpha-2a, interferon, alpha-2b, interferon beta,        interferon gamma-1a or interferon gamma-n1. Other agents include        filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10,        aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab,        denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod,        lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim,        OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin,        tositumomab, Virulizin, Z-100, epratuzumab, mitumomab,        oregovomab, pemtumomab, and Provenge;    -   Biological response modifiers are agents that modify defense        mechanisms of living organisms or biological responses, such as        survival, growth, or differentiation of tissue cells to direct        them to have anti-tumor activity. Such agents include krestin,        lentinan, sizofiran, picibanil, or ubenimex;    -   Other anticancer agents include alitretinoin, ampligen,        atrasentan, bexarotene, bortezomib, Bosentan, calcitriol,        exisulind, finasteride, fotemustine, ibandronic acid,        miltefosine, mitoxantrone, I-asparaginase, procarbazine,        dacarbazine, hydroxycarbamide, pegaspargase, pentostatin,        tazarotne, TLK-286, Velcade, Tarceva, or tretinoin;    -   Other anti-angiogenic compounds include acitretin, fenretinide,        thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide,        combretastatin A-4, endostatin, halofuginone, rebimastat,        removab, Revlimid, squalamine, ukrain and Vitaxin;    -   Platinum-coordinated compounds include but are not limited to,        cisplatin, carboplatin, nedaplatin, or oxaliplatin;    -   Camptothecin derivatives include but are not limited to        camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin,        irinotecan, SN-38, edotecarin, and topotecan;    -   Tyrosine kinase inhibitors are Iressa or SU5416;    -   Antibodies include Herceptin, Erbitux, Avastin, or Rituximab;        and    -   Interferons include interferon alpha, interferon alpha-2a,        interferon, alpha-2b, interferon beta, interferon gamma-1a or        interferon gamma-n1.

“Abnormal cell growth”, as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes theabnormal growth of: (1) tumor cells (tumors) that proliferate byexpressing a mutated tyrosine kinase or overexpression of a receptortyrosine kinase; (2) benign and malignant cells of other proliferativediseases in which aberrant tyrosine kinase activation occurs; (4) anytumors that proliferate by receptor tyrosine kinases; (5) any tumorsthat proliferate by aberrant serine/threonine kinase activation; and (6)benign and malignant cells of other proliferative diseases in whichaberrant serine/threonine kinase activation occurs.

The compounds of the present invention are potent inhibitors of the FAKprotein tyrosine kinases, and thus are all adapted to therapeutic use asantiproliferative agents (e.g., anticancer), antitumor (e.g., effectiveagainst solid tumors), antiangiogenesis (e.g., stop or preventproliferationation of blood vessels) in mammals, particularly in humans.In particular, the compounds of the present invention are useful in theprevention and treatment of a variety of human hyperproliferativedisorders such as malignant and benign tumors of the liver, kidney,bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic,lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, headand neck, and other hyperplastic conditions such as benign hyperplasiaof the skin (e.g., psoriasis) and benign hyperplasia of the prostate(e.g., BPH). It is, in addition, expected that a compound of the presentinvention may possess activity against a range of leukemias and lymphoidmalignancies.

In one preferred embodiment of the present invention cancer is selectedfrom lung cancer, bone cancer, pancreatic cancer, gastric, skin cancer,cancer of the head or neck, cutaneous or intraocular melanoma, uterinecancer, ovarian cancer, gynecological, rectal cancer, cancer of the analregion, stomach cancer, colon cancer, breast cancer, uterine cancer,carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, Hodgkin's Disease, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system, cancer of the thyroid gland,cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma ofsoft tissue, cancer of the urethra, cancer of the penis, squamous cell,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,cancer of the bladder, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain,pituitary adenoma, or a combination of one or more of the foregoingcancers.

In a more preferred embodiment cancer is selected a solid tumor, suchas, but not limited to, breast, lung, colon, brain, prostate, stomach,pancreatic, ovarian, skin (melanoma), endocrine, uterine, testicular,and bladder.

The compounds of the present invention may also be useful in thetreatment of additional disorders in which aberrant expressionligand/receptor interactions or activation or signalling events relatedto various protein tyrosine kinases, are involved. Such disorders mayinclude those of neuronal, glial, astrocytal, hypothalamic, and otherglandular, macrophagal, epithelial, stromal, and blastocoelic nature inwhich aberrant function, expression, activation or signalling of theerbB tyrosine kinases are involved. In addition, the compounds of thepresent invention may have therapeutic utility in inflammatory,angiogenic and immunologic disorders involving both identified and asyet unidentified tyrosine kinases that are inhibited by the compounds ofthe present invention.

A particular aspect of this invention is directed to methods fortreating or preventing a condition that presents with low bone mass in amammal (including a human being) which comprise administering to amammal in need of such treatment a condition that presents with low bonemass treating amount of a Formula I compound or a pharmaceuticallyacceptable salt of said compound.

This invention is particularly directed to such methods wherein thecondition that presents with low bone mass is osteoporosis, frailty, anosteoporotic fracture, a bone defect, childhood idiopathic bone loss,alveolar bone loss, mandibular bone loss, bone fracture, osteotomy,periodontitis or prosthetic ingrowth.

A particular aspect of this invention is directed to methods fortreating osteoporosis in a mammal (including a human being) whichcomprise administering to a mammal in need of such treatment anosteoporosis treating amount of a Formula I compound or apharmaceutically acceptable salt of said compound.

Another aspect of this invention is directed to methods for treating abone fracture or an osteoporotic fracture in a mammal which compriseadministering to a mammal in need of such treatment a bone fracturetreating or an osteoporotic fracture treating amount of a Formula Icompound or a pharmaceutically acceptable salt of said compound.

The term “osteoporosis” includes primary osteoporosis, such as senile,postmenopausal and juvenile osteoporosis, as well as secondaryosteoporosis, such as osteoporosis due to hyperthyroidism or Cushingsyndrome (due to corticosteroid use), acromegaly, hypogonadism,dysosteogenesis and hypophospatasemia.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. The daily dosage ofthe compound of formula (I)/salt/solvate (active ingredient) may be inthe range from 1 mg to 1 gram, preferably 1 mg to 250 mg, morepreferably 10 mg to 100 mg.

The present invention also encompasses sustained release compositions.

As noted above, the compounds of the invention are useful for treatingabnormal cell growth such, e.g., cancer. Without being limited bytheory, Applicants believe that the compounds of the invention areuseful for treating or preventing abnormal cell growth by inhibiting theFAK kinases.

In Vitro and In Vivo Assays

As noted above, the compounds of the invention are useful as inhibitorsof receptor tyrosine kinases such as, e.g., FAK, Aurora-1, Aurora-2, HgKand Pyk. Methods for determining the in vitro and in vivo activity ofthese compounds inhibitors of receptor tyrosine kinases are describedbelow:

A. In-Vitro Activity of FAK:

The in vitro activity of the compounds of the compounds of the inventionmay be determined by the following procedure. More particularly, thefollowing assay provides a method to determine whether compounds of thecompounds of the invention inhibit the tyrosine kinase activity of thecatalytic construct FAK(410-689). The assay is an ELISA-based format,measuring the inhibition of poly-glu-tyr phosphorylation byFAK(410-689). The assay protocol has three parts:

I. Purification and cleavage of His-FAK(410-689)

II. FAK410-689 (a.k.a. FAKcd) Activation

III. FAKcd Kinase ELISA

Materials:

-   -   Ni-NTA agarose (Qiagen)    -   XK-16 column (Amersham-Pharmacia)    -   300 mM Imidizole    -   Superdex 200 HiLoad 16/60 prep grade column (Amersham Biotech.)    -   Antibody: Anti-Phosphotyrosine HRP-Conjugated Py20 (Transduction        labs)    -   FAKcd: Purified and activated in house    -   TMB Microwell Peroxidase Substrate (Oncogene Research Products        #CL07)    -   BSA: Sigma #A3294    -   Tween-20: Sigma #P1379    -   DMSO: Sigma #D-5879    -   D-PBS: Gibco #14190-037        Reaqents for Purification:    -   Buffer A: 50 mM HEPES pH 7.0    -   500 mM NaCl    -   0.1 mM TCEP    -   Complete™ protease inhibitor cocktail tablets (Roche)    -   Buffer B: 25 mM HEPES pH 7.0    -   400 mM NaCl    -   0.1 mM TCEP    -   Buffer C: 10 mM HEPES pH 7.5    -   200 mM Ammonium Sulfate    -   0.1 mM TCEP        Reagents for Activation:    -   FAK(410-689): 3 tubes of frozen aliquots at 150 μl/tube for a        total of 450 μl at 1.48 mg/ml (660 μg)    -   His-Src(249-524): ˜0.74 mg/ml stock in 10 mM HEPES, 200 mM        (NH4)2SO4    -   Src reaction buffer (Upstate Biotech):    -   100 mM Tris-HCl pH7.2    -   125 mM MgCl2    -   25 mM MnCl2    -   2 mM EDTA    -   250 μM Na3VO4    -   2 mM DTT    -   Mn2+/ATP cocktail (Upstate Biotech)    -   75 mM MnCl2    -   500 μM ATP    -   20 mM MOPS pH 7.2    -   1 mM Na3VO4    -   25 mM—glycerol phosphate    -   5 mM EGTA    -   1 mM DTT    -   ATP: 150 mM stock    -   MgCl2: 1 M Stock    -   DTT: 1 M stock        Reagents for FAKcd Kinase ELISA:    -   Phosphorylation Buffer:    -   50 mM HEPES, pH 7.5    -   125 mM NaCl    -   48 mM MgCl2    -   Wash Buffer: TBS+0.1% Tween-20.    -   Blocking Buffer:    -   Tris Buffer Saline    -   3% BSA    -   0.05% Tween-20, filtered    -   Plate Coating Buffer:    -   50 mg/ml Poly-Glu-Tyr (Sigma #P0275) in Phosphate buffer Saline        (DPBS).    -   ATP: 0.1M ATP in H2O or HEPES, pH7    -   Note: ATP Assay Buffer:    -   Make up as 75 uM ATP in PBS, so that 80 μl in    -   120 μl reaction volume=50 μM final ATP concentration.        I. Purification of His-FAKcd(410-689):        1. Resuspend 130 g baculovirus cell paste containing the over        expressed His-FAKcd410-689 recombinant protein in 3 volumes        (400 ml) of Buffer A.        2. Lyse cells with one pass on a microfluidizer.        3. Remove cell debris by centrifugation at 4° C. for 35 minutes        at 14,000 rpm in a Sorval SLA-1500 rotor.        4. Transfer the supernatant to a clean tube and add 6.0 ml of        Ni-NTA agarose (Qiagen).        5. Incubate the suspension with gentle rocking at 4° C. for 1        hour.        6. Centrifuge suspension at 700×g in a swinging bucket rotor.        7. Discard the supernatant and resuspend the agarose beads in        20.0 ml of Buffer A.        8. Transfer the beads to an XK-16 column (Amersham-Pharmacia)        connected to a FPLC™.        9. Wash the agarose-beads with 5 column volumes of Buffer A and        elute off the column with a step gradient of Buffer A containing        300 mM Imidizole.        10. Perform a buffer exchange of the eluted fractions into        Buffer B.        11. Following buffer exchange, pool the fractions and add        thrombin at a 1:300 (w/w) ratio and incubated overnight at        13° C. to remove the N-terminal His-tag (His-FAK410-698 à        FAK410-689 (a.k.a. FAKcd)).        12. Add the reaction mixture back onto the Ni-NTA column        equilibrated with Buffer A and collect the flow-through.        13. Concentrate the flow-through down to 1.7 ml and load        directly onto a Superdex 200 HiLoad 16/60 prep grade column        equilibrated with Buffer C. The desired protein elutes between        85-95 ml.        14. Aliquot the FAKcd protein and store frozen at −80° C.        II. FAK Activation        1. To 450 ul of FAK(410-689) at 1.48 mg/ml (660 μg) add the        following:        30 μl of 0.037 mg/ml (1 μM) His-Src(249-524)        30 μl of 7.5 mM ATP        12 μl of 20 mM MgCl2        10 μl Mn2+/ATP cocktail (UpState Biotech.)        4 μl of 6.7 mM DTT        60 μl Src Reaction Buffer (UpState Biotech.)        2. Incubate Reaction for at least 3 hours at room temperature        At time t0, almost all of the FAK(410-689) is singly        phosphorylated. The second phosphorylation is slow. At t120        (t=120 minutes), add 10 μl of 150 mM ATP.        T0=(Start) 90% singly phosphorylated FAK(410-689) (1 PO4)        T43=(43 min) 65% singly phosphorylated (1 PO4), 35% doubly        phosphorylated (2 PO4)        T90=(90 min) 45% 1 PO4, 55% 2 PO4        T150=15% 1 PO4, 85% 2 PO4        T210=<10% 1 PO4, >90% 2 PO4 desalted sample        3. Add 180 μl aliquots of the desalted material to NiNTA spin        column and incubate on spin column        4. Spin at 10 k rpm (microfuge), for 5 minutes to isolate and        collect flow through (Activated FAK(410-689)) and remove His-Src        (captured on column)        III. FAKcd Kinase ELISA        1. Coat 96-well Nunc MaxiSorp plates with poly-glu-tyr (pGT) at        10 μg/well: Prepare 10 μg/ml of pGT in PBS and aliquot 100        μl/well. Incubate the plates at 37° C. overnight, aspirate the        supernatant, wash the plates 3 times with Wash Buffer, and flick        to dry before storing at 4° C.        2. Prepare compound stock solutions of 2.5 mM in 100% DMSO. The        stocks are subsequently diluted to 60× of the final        concentration in 100% DMSO, and diluted 1:5 in Kinase        Phosphorylation Buffer.        3. Prepare a 75 μM working ATP solution in Kinase        phosphorylation buffer. Add 80 μl to each well for a final ATP        concentration of 50 μM.        4. Transfer 10 μl of the diluted compounds (0.5 log serial        dilutions) to each well of the pGT assay plate, running each        compound in triplicates on the same plate.        5. Dilute on ice, FAKcd protein to 1:1000 in Kinase        Phosphorylation Buffer. Dispense 30 μl per well.        6. Note: Linearity and the appropriate dilution must be        pre-determined for each batch of protein. The enzyme        concentration selected should be such that quantitation of the        assay signal will be approximately 0.8-1.0 at OD450, and in the        linear range of the reaction rate.        7. Prepare both a No ATP control (noise) and a No Compound        Control (Signal):        8. (Noise) One blank row of wells receives 10 μl of 1:5 diluted        compounds in DMSO, 80 μl of Phosphorylation buffer (minus ATP),        and 30 μl FAKcd solution.        9. (Signal) Control wells receive 10 μl of 1:5 diluted DMSO        (minus Compound) in Kinase phosphorylation buffer, 80 μl of 75        uM ATP, and 30 μl of 1:1000 FAKcd enzyme.        10. Incubate reaction at room temperature for 15 minutes with        gentle shaking on a plate shaker.        11. Terminate the reaction by aspirating off the reaction        mixture and washing 3 times with wash buffer.        12. Dilute phospho-tyrosine HRP-conjugated (pY20HRP) antibody to        0.250 μg/ml (1:1000 of Stock) in blocking buffer. Dispense 100        μl per well, and incubate with shaking for 30 minutes at 25°.        13. Aspirate the supernatant and wash the plate 3 times with        wash buffer.        14. Add 100 μl per well of room temperature TMB solution to        initiate color development. Color development is terminated        after approximately 15-30 sec. by the addition of 100 μl of        0.09M H2SO4 per well.        15. The signal is quantitated by measurement of absorbance at        450 nm on the BioRad ricroplate reader or a microplate reader        capable of reading at OD450.        16. Inhibition of tyrosine kinase activity would result in a        reduced absorbance signal. The signal is typically 0.8-1.0 OD        units. The values are reported as IC50s, μM concentration.        FAK Inducible cell-based ELISA: Final Protocol        Materials:

Reacti-Bind Goat Anti-Rabbit Plates 96-well (Pierce Product#15135ZZ@115.00 USD)

FAKpY397 rabbit polyclonal antibody (Biosource #44624 @315.00 USD)

ChromePure Rabbit IgG, whole molecule (Jackson Laboratories #001-000-003@60/25 mg USD)

UBI aFAK clone 2A7 mouse monoclonal antibody (Upstate#05-182 @ 289.00USD)

Peroxidase-conjugated AffiniPure Goat Anti-Mouse IgG (Jackson Labs#115-035-146 @95/1.5 ml USD)

SuperBlock TBS (Pierce Product#37535ZZ @99 USD)

Bovine Serum Albumin (Sigma #A-9647 @117.95/100 g USD)

TMB Peroxidase substrate (Oncogene Research Products #CL07-100 ml @40.00USD)

Na3VO4 Sodium Orthovanadate (Sigma #S6508 @43.95/50 g USD)

MTT substrate (Sigma # M-2128 @25.95/500 mg USD)

Growth Media: DMEM+10% FBS, P/S, Glu, 750 μg/ml Zeocin and 50 μg/mlHygromycin (Zeocin InVitrogen #R250-05 @ 725 USD and HygromyconInVitrogen #R220-05 @ 150 USD)

Mifepristone InVitrogen # H110-01 @ 125 USD

Complete™ EDTA-free Protease Inhibitor pellet Boehringer Mannheim#1873580

FAK cell-based Protocol for selectivity of kinase-dependentphosphoFAKY397

Procedure:

An inducible FAK cell-based assay in ELISA format for the screening ofchemical matter to identify tyrosine kinase specific inhibitors wasdeveloped. The cell-based assay exploits the mechanism of theGeneSwitch™ system (InVitrogen) to exogenously control the expressionand phosphorylation of FAK and the kinase-dependent autophosphorylationsite at residue Y397.

Inhibition of the kinase-dependent autophosphorylation at Y397 resultsin a reduced absorbance signal at OD450. The signal is typically 0.9 to1.5 OD450 units with the noise falling in the range of 0.08 to 0.1 OD450units. The values are reported as IC50s, μM concentration.

On day 1, grow A431⋅FAKwt in T175 flasks. On the day prior to runningthe FAK cell-assay, seed A431⋅FAKwt cells in growth media on 96-wellU-bottom plates. Allow cells to sit at 37° C., 5% CO2 for 6 to 8 hoursprior to FAK induction. Prepare Mifepristone stock solution of 10 μM in100% Ethanol. The stock solution is subsequently diluted to 10× of thefinal concentration in Growth Media. Transfer 10 μl of this dilution(final concentration of 0.1 nM Mifepristone) into each well. Allow cellsto sit at 37° C., 5% CO2 overnight (12 to 16 hours). Also, preparecontrol wells without Mifepristone induction of FAK expression andphosphorylation.

On day 2, coat Goat Anti-Rabbit plate(s) with 3.5 μg/ml ofphosphospecific FAKpY397 polyclonal antibody prepared in SuperBlock TBSbuffer, and allow plate(s) to shake on a plate shaker at roomtemperature for 2 hours. Optionally, control wells may be coated with3.5 μg/ml of control Capture antibody (Whole Rabbit IgG molecules)prepared in SuperBlock TBS. Wash off excess FAKpY397 antibody 3 timesusing buffer. Block Anti-FAKpY397 coated plate(s) with 200 μl per wellof 3% BSA/0.5% Tween Blocking buffer for 1 hour at room temperature onthe plate shaker. While the plate(s) are blocking, prepare compoundstock solutions of 5 mM in 100% DMSO. The stock solutions aresubsequently serially diluted to 100× of the final concentration in 100%DMSO. Make a 1:10 dilution using the 100× solution into growth media andtransfer 10 μl of the appropriate compound dilutions to each wellcontaining either the FAK induced or uninduced control A431 cells for 30minutes at 37° C., 5% CO2. Prepare RIPA lysis buffer (50 mM Tris-HCl,pH7.4, 1% NP-40, 0.25% Na-deoxycholate, 150 mM NaCl, 1 mM EDTA, 1 mMNa3VO4, 1 mM NaF, and one Complete™ EDTA-free protease inhibitor pelletper 50 ml solution). At the end of 30 minutes compound treatment, washoff compound 3 times using TBS-T wash buffer. Lyse cells with 100μl/well of RIPA buffer.

To the coated plate, remove blocking buffer and wash 3 times using TBS-Twash buffer. Using a 96-well automated microdispenser, transfer 100 μlof whole cell-lysate (from step 6) to the Goat Anti-Rabbit FAKpY397coated plate(s) to capture phosphoFAKY397 proteins. Shake at roomtemperature for 2 hours. Wash off unbound proteins 3 times using TBS-Twash buffer. Prepare 0.5 μg/ml (1:2000 dilution) of UBI aFAK detectionantibody in 3% BSA/0.5% Tween blocking buffer. Dispense 100 μl of UBIaFAK solution per well and shake for 30 minutes at room temperature.Wash off excess UBI aFAK antibody 3 times using TBS-T wash buffer.Prepare 0.08 μg/ml (1:5000 dilution) of secondary Anti-Mouse Peroxidase(Anti-2MHRP) conjugated antibody. Dispense 100 μl per well of theAnti-2MHRP solution and shake for 30 minutes at room temperature. Washoff excess Anti-2MHRP antibody 3 times using TBS-T wash buffer. Add 100μl per well of room temperature TMB substrate solution to allow forcolor development. Terminate the TMB reaction with 100 μl per well ofTMB stop solution (0.09M H2SO4) and quantitate the signal by measurementof absorbance at 450 nm on the BioRad microplate reader.

Additional FAK cell assays are hereby incorporated by reference fromWO02004/027018.

In a preferred embodiment, the compounds of the present invention havean in vitro activity as determined by a kinase assay, e.g., such as thatdescribed herein, of less than 500 nM. Preferably, the compounds have anIC50 of less than 25 nM in the kinase assay, and more preferably lessthan 10 nM. In a further preferred embodiment, the compounds exhibit anIC50 in a FAK cell based assay, e.g., such as that described herein, ofless than 1 μM, more preferably less than 100 nM, and most preferablyless than 25 nM.

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, and rectal administration.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to about 7 g/day,preferably about 0.2 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

The active compound may be applied as a sole therapy or may involve oneor more other anti-tumour substances, for example those selected from,for example, mitotic inhibitors, for example vinblastine; alkylatingagents, for example cis-platin, carboplatin and cyclophosphamide;anti-metabolites, for example 5-fluorouracil, cytosine arabinoside andhydroxyurea, or, for example, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex® (tamoxifen) or, for example anti-androgens such as Casodex®(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefor,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

All patents, applications, publications, test methods, literature, andother materials cited herein are hereby incorporated herein by referencein their entireties.

EXAMPLES General Methods

HPLC:

Where HPLC chromatography is referred to in the preparations andexamples below, the general conditions used, unless otherwise indicated,are as follows. The column used is a ZORBAX™ RXC18 column (manufacturedby Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. Thesamples are run on a Hewlett Packard-1100 system. A gradient solventmethod is used running 100 percent ammonium acetate/acetic acid buffer(0.2 M) to 100 percent acetonitrile over 10 minutes. The system thenproceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutesand then 100 percent buffer solution for 3 minutes. The flow rate overthis period is a constant 3 mL/minute.

Preparation of Intermediates

The groups attached to the 4 position of the pyridine core were preparedby the methods described below for compounds B1-B19.

Preparation of N-(3-aminomethyl-phenyl)-N-methyl-methanesulfonamideacetate (B1)

Step 1. Preparation of N-(3-cyano-phenyl)-methanesulfonamide (B1-1)

A solution of 3-amino benzonitrile (10 g, 84.64 mmol) in pyridine (160mL) was cooled to 0° C. and methane sulphonyl chloride (8.6 mL, 74.8mmol) was added. The reaction mixture was allowed to warm to 25° C. andstirred for about 20 hours. The reaction mixture was then concentrated,and the resultant residue was dissolved in ethyl acetate (EtOAc) (250mL), washed with 2N HCl (50 mL), brine (25 mL), and dried over anhydrousNa₂SO₄. The solution was then concentrated to provide (B1-1) as a brownsolid. Yield: 17.1 g. ¹HNMR (d₆-DMSO) δ: 10.25 (s, 1H), 7.45-7.65 (m,4H) and 3.1 (s, 3H). Mass: (M−1) 195 calculated for C₈H₈N₂O₂S.

Step. 2. Preparation of N-(3-cyano-phenyl)-N-methyl-methanesulfonamide(B1-2)

A mixture of benzyltriethylammonium chloride (BTEAC) (2.44 g, 10.7 mmol)and B1-1 (21 g, 107.1 mmol) in tetrahydrofuran (THF) (250 mL) and 40%NaOH solution (250 mL) was cooled to 10° C., treated with methyl iodide(8.6 mL, 139.0 mmol), and allowed to warm to 25° C. After about 20 hoursthe THF was removed by distillation, and the concentrated mixture wasextracted with dichloromethane (DCM) (3×200 mL). The combined organiclayers were washed with water (100 mL), brine (50 mL), dried overanhydrous sodium sulfate, and concentrated. The resultant residue wasthen purified by column chromatography (60-120 mesh silica gel; 20%EtOAc in hexane as eluting solvent) to provide B1-2 as a white solid.Yield: 20 g, 89.3%. ¹HNMR (d₆-DMSO) δ: 7.9 (s, 1H), 7.7-7.84 (m, 2H),7.52-7.65 (m, 2H), 3.3 (s, 3H) and 3.02 (s, 3H). Mass: (M+1) 211calculated for C₉H₁₀N₂O₂S.

Step 3

A solution of B1-2 (20 g, 95.12 mmol) in THF(100 mL) and acetic acid(400 mL) was charged to a Parr reactor. The contents of the reactor werethen treated with 10% Pd/C (10.12 g) and hydrogenated at 50 Psi hydrogenpressure and 25° C. for 4 hours. The contents of the reactor werefiltered through a bed of Celite® and washed with ethanol (50 mL). Thecombined filtrates were then concentrated under reduced pressure, andthe resultant residue was azeotroped with EtOAc (3×50 mL). The resultantoily mass was dissolved in EtOAc and allowed stand at 25° C. for about20 hours. The resultant white solids were collected by filtration anddried to provide B1 as the acetate salt. Yield: 15.2 g, 60%. ¹HNMR(d₆-DMSO) δ: 7.2-7.45 (m, 4H), 4.6-5.65 (broad, 4H), 3.75 (s, 2H), 3.2(s, 3H), 2.95 (s, 3H) and 1.9 (s, 3H). Mass: (M+1) 215 calculated forC₉H₁₄N₂O₂S. HPLC Purity: 99.1%.

Preparation of N-(3-aminomethyl-pyrazin-2-yl)-N-methyl-methanesulfonamide acetate (B2)

Step 1. Preparation of N-(3-cyano-pyrazin-2-yl)-N-methyl-methanesulfonamide (B2-1)

A solution of chloropyrazine-2-carbonitrile (4.2 g, 30.21 mmol) inacetonitrile (200 mL) at 25° C. was treated sequentially with Cs₂CO₃(13.7831 g, 42.293 mmol) and N-methyl-methane sulfonamide (3.957 g,36.25 mmol). The mixture was then heated to 80° C. After about 20 hoursthe mixture was cooled to 25° and filtered. The solids were washed withEtOAc (3×25 mL) and the combined filtrates were concentrated. Theresultant residue was treated with water (50 mL) and extracted withEtOAc (3×75 mL). The combined organic layers were washed with water (50mL), brine, dried over anhydrous sodium sulfate and concentrated. Theresultant residue was purified by column chromatography (100-200 meshsilica gel; 40% EtOAc in petroleum ether as eluting solvent) to provideB2-1 as a pale brown liquid. Yield: 4.7 g, 73.43%). ¹HNMR (CDCl₃) δ:8.92 (d, 2H), 3.4 (s, 3H) and 3.25 (s, 3H). Mass: (M+1) 213 calculatedfor C₇H₈N₄O₂S. (Note: The product contained unreactedN-methanesulfonamide as an impurity. The product was used withoutfurther purification to prepare B2 in the step described below.

Step 2

A suspension of B2-1 (5.345 g, 23.21 mmol) in 2N methanolic NH₃ (566.7mL) in a Parr reactor was treated with 10% Pd/C (395 mg, 3.78 mmol), andthe contents of the reactor were hydrogenated at 45 Psi hydrogenpressure and 25° C. for 3 hours. The contents of the reactor were thenfiltered through a bed of Celite®, washed with methanol (MeOH), andconcentrated. The resultant residue was treated with EtOAc (25 mL) andacetic acid (1.5 g), stirred at 25° C., and concentrated. The resultantresidue was treated with EtOAc (100 mL) and allowed to stand at 25° C.for about 20 hours. The resultant solids were collected, washed withEtOAc, and dried to provide B2. Yield: 3.5 g, 64.3%. IR (cm⁻¹): 3453,3222, 2937, 3859, 1641, 1560, 1405, 1340 and 1155. ¹HNMR (d₆-DMSO) δ:8.7 (s, 1H), 8.5 (s, 1H), 5.3-5.8 (broad, 2H), 4.0 (s, 2H), 3.2 (s, 3H),3.12 (s, 3H) and 1.84 (s, 3H). Mass: (M+1) 217 calculated forC₇H₁₂N₄O₂S.

Preparation of N-(2-aminomethyl-phenyl)-N-methyl-methanesulfonamideacetate (B3)

Step 1. Preparation of N-(2-cyano-phenyl)-N-dimethanesulfonamide (B3-1)

A solution of 2-amino benzonitrile (10 g, 8.46 mmol) in pyridine (250mL) at 25° C. was treated drop-wise over 30 minutes with methanesulphonyl chloride (21.33 g, 18.62 mmol). The reaction mixture was thenstirred at 25° C. for about 20 hours and concentrated The resultantresidue was dissolved in EtOAc (200 mL), washed with 2 N HCl (200 mL)and brine (30 mL), and dried over anhydrous sodium sulfate. The solutionwas then concentrated to provide B3-1 as a yellow solid. Yield: 20.7 g,89%. ¹HNMR (d₆-DMSO) δ: 8.06 (d, 1H), 7.82-7.85 (m, 2H), 7.7-7.75 (m,1H), 3.62 (s, 6H).

Step 2. Preparation of N-(2-cyano-phenyl)-N-methyl-methanesulfonamide(B3-2)

A solution of B3-1 (4 g, 1.45 mmol) in THF (30 mL) at 25° C. was treatedwith 40% NaOH solution (30 mL) and BTEAC (0.331 g, 0.145 mmol) andstirred vigorously for 30 minutes. The mixture was then treated withmethyl iodide (2.48 g, 1.7 mmol) and stirred at 25° C. for about 20hours. The THF was removed under reduced pressure and the mixtureextracted with DCM (3×50 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, and concentrated toprovide B3-2 as a pale yellow solid. Yield: 3 g, 96%. ¹HNMR (CDCl₃) δ:7.62-7.8 (m, 2H), 7.55-7.56 (m, 1H), 7.4-7.52 (m, 1H), 3.4 (s, 3H) and3.15 (s, 3H). Mass: (M−1) 209 calculated for C₉H₁₀N₂O₂S. The product wasused without further purification to prepare B3 in the step describedbelow.

Step 3

A solution of B3-2 (2 g, 9.5 mmol) in a mixture of acetic acid (100 mL)and TI-IF (25 mL) was charged to a Parr shaker. The contents of thereactor were treated with 10% Pd/C (1.01 g) and hydrogenated at 60 Psihydrogen pressure and 25° C. for 3.5 hours. The contents of the reactorwere then filtered through a bed of Celite® and washed with MeOH (20mL). The combined filtrates were then concentrated. The resultantresidue was azeotroped with toluene (2×20 mL) and EtOAc (20 mL) anddried under vacuum to provide B3 as a white solid. Yield: 1.9 g, 95%.¹HNMR (d₆-DMSO) δ: 7.5-7.62 (m, 1H), 7.25-7.5 (m, 3H), 3.92-5.6 (broad,3H), 3.8 (s, 2H), 3.16 (s, 3H), 3.04 (s, 3H) and 1.9 (s, 2H). Mass:(M+1) 215 calculated for C₉H₁₄N₂O₂S. HPLC Purity: 98.8%.

Preparation ofN-(2-aminomethyl-pyridin-3-yl)-N-methyl-methanesulfonamide acetate Salt(B4)

Step 1. Preparation of 6-chloro-pyridin-3-ylamine (B4-1)

A solution of 2-chloro-5-nitro pyridine (30 g, 189 mmol) in MeOH (600mL) was charged to a Parr reactor. The contents of the reactor weretreated with Raney nickel (2 g) and hydrogenated at 60 Psi hydrogenpressure and 25° C. for 16 hours. The contents of the reactor were thenfiltered through a Celite® bed and washed with MeOH (100 mL). Thecombined filtrates were concentrated, and the resultant residue waspurified by column chromatography (60-120 mesh silica gel column; 10%MeOH in CHCl₃ as eluting solvent) to provide B4-1 as a pale yellowsolid. Yield: 19 g, 78%. ¹HNMR (CDCl₃) δ: 7.85 (d, 1H), 7.1 (d, 1H),6.95 (dd, 1H) and 3.52-3.98 (broad s, 2H).

Step 2. Preparation of N-(6-chloro-pyridin-3-yl)-methanesulfonamide(B4-2)

A solution of B4-1 (38 g, 295.7 mmol) and pyridine (28 g, 354 mm) in DCM(874 mL) at 10° C. was treated drop-wise over 30 minutes with methanesulphonyl chloride (37.2 g, 325 mmol). The reaction mixture was allowedto warm to 25° C., and stirred at 25° C. for 20 hours. The mixture wasthen treated with DCM (300 mL) and washed with water (1500 mL) andbrine. The organic layer was dried over anhydrous sodium sulfate andconcentrated. The resultant residue was washed with petroleum ether (80mL), filtered, and dried to provide B4-2 as an off-white solid. Yield:36 g, 60%. ¹HNMR (d₆-DMSO) δ: 10.12 (s, 1H), 8.22 (d, 1H), 7.65 (dd,1H), 7.46 (d, 1H) and 3.08 (s, 3H).

Step 3. Preparation ofN-(6-chloro-pyridin-3-yl)-N-methyl-methanesulfonamide (B4-3)

A solution of B4-2 (13 g, 62.8 mmol), BTEAC (1.42 g, 6.2 mmol) and 40%aq. NaOH (117 mL) in THF (117 mL) at 0° C. was treated drop-wise over 30minutes with methyl iodide (10.6 g, 75.3 mmol). The reaction mixture wasallowed to warm to 25° C. and stirred for an additional 3 hours. Themixture was then treated with THF (100 mL), and the resultant organiclayer was collected. The aqueous layer was extracted with EtOAc (2×100mL), and the combined organic layers were washed with 1N NaOH and brine.The organic layer was dried over anhydrous sodium sulfate andconcentrated. The resultant residue was then triturated with petroleumether to provide B4-3 as a pale yellow solid. Yield: 12 g, 86%. ¹HNMR(CDCl₃) δ: 8.4 (d, 1H), 7.72 (dd, 1H), 7.35 (d, 1H), 3.38 (s, 3H) and2.88 (s, 3H). Mass: (M+1) 221 calculated for C₇H₉ClN₂O₂S.

Step 4. Preparation ofN-(6-chloro-1-hydroxy-pyridin-3-yl)-N-methyl-methanesulfonamide (B4-4)

A solution of B4-3 (15 g, 68.1 mmol) in DCM (172 mL) was cooled to 0° C.and treated slowly over 10 minutes with a solution of 77%m-chloroperoxybenzoic acid (MCPBA) (27.9 g, 124 mm) in DCM (200 mL). Therate of addition was controlled so that the temperature of the reactionmixture did not exceed 3 to 5° C. The reaction mixture was allowed towarm to 25° C. and stirred at 25° C. for 20 hours. The mixture was thencooled to 0° C. and treated with 1N NaOH (300 mL). The resultant organiclayer was collected and washed with 1N NaOH (100 mL) and 10% sodiumsulfite (100 mL). The organic layer was then dried over anhydrous Na₂SO₄and concentrated to provide B4-4 as a white crystalline solid. Yield: 8g, 49%. ¹HNMR (d₆-DMSO) δ: 8.55 (s, 1H), 7.85 (d, 1H), 7.46 (dd, 1H),3.26 (s, 3H) and 3.1 (s, 3H). Mass: (M+1) 237 calculated forC₇H₁₁ClN₂O₃S.

Step 5. Preparation ofN-(6-chloro-2-cyano-pyridin-3-yl)-N-methyl-methanesulfonamide (B4-5)

Dimethylsulfate (3.2 mL) was cooled to 0° C. and treated portion-wisewith B4-4 (8 g, 33.6 mmol) over 3 hours. The resultant suspension wasallowed to warm to 25° and maintained at 25° C. for 16 hours. Theresulted gummy mass was then washed with diethyl ether. The resultantwhite residue was dissolved in water (37.6 mL) and added drop-wise over30 minutes to an aqueous solution of sodium cyanide (6.5 g, 134.4 mm) at10° C. The reaction mixture was allowed to warm to 25° C., and it wasmaintained at 25° C. for 16 hours. The resultant brown solids werecollected and dissolved in EtOAc (200 mL). The organic solution was thenwashed with water (500 mL) and brine, and dried over anhydrous sodiumsulfate. The organic solution was concentrated, and the resultantresidue was purified by column chromatography (silica gel; 10% MeOH inCHCl₃ as eluting solvent) to provide B4-5 as a white solid. Yield: 2.5g, 30%. ¹HNMR (d₆-DMSO) δ: 8.38 (d, 1H), 8.02 (d, 1H), 3.3 (s, 3H) and3.28 (s, 3H).

Step 6

A solution of B4-5 (2.5 g, 10.2 mmol) in a mixture of THF (80 mL) andacetic acid (200 mL) was charged to a Parr reactor. The contents of theParr reactor were then treated with 10% Pd/C (2.4 g, 22.4 mmol) andhydrogenated at 60 Psi hydrogen pressure and 25° C. for 16 hours. Thecontents of the reactor were filtered through a Celite® bed and washedwith MeOH (100 mL). The combined organic filtrates were concentrated,and the resultant residue was azeotroped with EtOAc (2×50 mL). Theresultant solids were collected and dried to provide B4 as an off-whitesolid. Yield: 2.0 g, 95%. IR (cm⁻¹): 3438, 3245, 2994, 2601, 1590, 1467,1328, 1151 and 1047. ¹HNMR (d₆-DMSO) δ: 8.65 (d, 1H), 8.25-8.55 (broads, 2H), 8.15 (d, 1H), 7.5-7.7 (m, 1H), 4.0-4.42 (s, 2H), 3.25 (s, 3H)and 3.14 (s, 3H). Mass: (M+1) 216 calculated for C₈H₁₃N₃O₂S.

Preparation ofN-(3-Aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide acetate (B5)

Step 1. Preparation ofN-(3-cyano-pyridin-2-yl)-N-methyl-methanesulfonamide (B5-1)

A solution of 2-chloro-3-cyano-pyridine (10 g, 72.4 mmol) inacetonitrile (200 mL) at 25° C. was treated withN-methyl-methanesulfonamide (14 g, 128.2 mmol) and Cs₂CO₃ (33 g, 101.2mmol). The reaction mixture was slowly heated to 80° C. and maintainedat 80° C. for 8 hours. The reaction mixture was then cooled to 25 C,filtered through a Celite® bed, and concentrated. The resultant residuewas treated with water (300 mL) and extracted with EtOAc (3×200 mL). Thecombined organic layers were washed with brine, dried over sodiumsulfate, treated with carbon, and filtered. The filtrate was thenconcentrated, and the resultant residue was triturated with ether (100mL). The resultant solids were collected and dried to provide B5-1 as anoff-white solid. Yield: 7 g, 46%. ¹HNMR (CDCl₃) δ: 8.6-8.72 (m, 1H),8.02-8.12 (d, 1H), 7.3-7.45 (m, 1H), 3.4 (s, 3H) and 3.2 (s, 3H). Mass:(M+1) 212 calculated for C₈H₉N₃O₂S. HPLC purity: 99.9%.

Step 2

A solution of B5-1 (10 g, 47.3 mmol) in ethanol was charged to a Parrreactor, and the contents of the reactor were treated with 300 mL of a2M ammonia solution in ethanol and 5% Pd/C (1.2 g). The contents of thereactor were then hydrogenated at 60 Psi hydrogen pressure and 37° C.for 3 hours and then at 30° C. for 20 hours. The contents of the reactorwere filtered through a Celite® bed and concentrated. The resultantresidue was treated with EtOAc, cooled to 20° C., and treated withacetic acid (10 mL). The mixture was then stirred for 10 minutes andconcentrated. The resultant residue was dissolved in EtOAc (150 mL) in aglass flask. The walls of the flask were then scratched, and whitesolids began to form. The solids were collected and washed with EtOAcfollowed by petroleum ether. The solids were then dried to provide B5.Yield: 11 g, 85%. ¹HNMR (CDCl₃) δ: 8.3-8.5 (m, 1H), 8.04 (d, 1H),7.4-7.55 (m, 1H), 6.02-7.15 (broad, 3H), 3.85 (s, 2H), 3.14 (d, 6H), 1.9(s, 3H). Mass: (M+1) 216 calculated for C₈H₁₃N₃O₂S.

Preparation of N-(2-Aminomethyl-phenyl)-N-methyl-methanesulfonamideacetate (B6)

Step 1. Preparation of N-(2-Cyano-phenyl)-N-dimethanesulfonamide (B6-1)

A solution of 2-amino benzonitrile (10 g, 8.46 mmol) in pyridine (250mL) was treated drop-wise at 25° C. over 30 minutes with methanesulphonyl chloride (21.33 g, 18.62 mmol). The reaction mixture was thenstirred at 25° C. for 20 hours and concentrated. The resultant residuewas dissolved in EtOAc (200 mL) and washed with 2 N HCl (200 mL) andbrine (30 mL). The solution was dried over anhydrous sodium sulfate andconcentrated to provide B6-1 as a yellow solid. Yield: 20.7 g, 89%.¹HNMR (d₆-DMSO): δ 8.06 (d, 1H), 7.82-7.85 (m, 2H), 7.7-7.75 (m, 1H),3.62 (s, 6H). The product was used without further purification toprepare B6-2 in the step described below.

Step 2. Preparation of N-(2-Cyano-phenyl)-N-methyl-methanesulfonamide(B6-2)

A solution of B6-1 (4 g, 1.45 mmol) in THF (30 mL) was treated with 40%NaOH (30 mL) and BTEAC (0.331 g, 0.145 mmol) at 25° C. and stirredvigorously for 30 minutes. The mixture was then treated with methyliodide (2.48 g, 1.7 mmol) and stirred at 25° C. for 20 hours. The THFwas removed under reduced pressure, and the concentrated mixture wasextracted with DCM (3×50 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, and concentrated toprovide B6-2 as pale yellow solid. Yield: 3 g, 96%. ¹H NMR (CDCl₃): δ7.62-7.8 (m, 2H), 7.55-7.56 (m, 1H), 7.4-7.52 (m, 1H), 3.4 (s, 3H) and3.15 (s, 3H). Mass: (M−1) 209 calculated for C₉H₁₀N₂O₂S. The product wasused without further purification to prepare B6 in the step describedbelow.

Step 3

A solution of B6-2 (2 g, 9.5 mmol) in a mixture of acetic acid (100 mL)and THF (25 mL) was charged to a Parr reactor. The contents of thereactor were treated with Pd/C (1.01 g) and hydrogenated at 60 Psihydrogen pressure and 25° C. for 3.5 hours. The mixture was thenfiltered through a bed of Celite® and washed with methanol (20 mL). Thecombined filtrates were concentrated, and the resultant residue wasazeotroped with toluene (2×20 mL) followed by EtOAc (20 mL). The residuewas then dried under reduced pressure to provide B6 as a white solid.Yield: 1.9 g, 95%. ¹HNMR (d₆-DMSO): δ 7.5-7.62 (m, 1H), 7.25-7.5 (m,3H), 3.92-5.6 (broad, 3H), 3.8 (s, 2H), 3.16 (s, 3H), 3.04 (s, 3H) and1.9 (s, 2H). Mass: (M+1) 215 calculated for C₉H₁₄N₂O₂S. HPLC Purity:98.8%.

Preparation of N-(2-Aminomethyl-phenyl)-methanesulfonamide acetate (B7)

Step 1. Preparation of N-(2-cyano-phenyl)-methanesulfonamide (B7-1)

A solution of B6-1 (4 g, 14.8 mmol) in THF (29.26 mL) was treated with40% aqueous NaOH (29.26 mL) and BTEAC (0.331 g, 1.45 mmol) and stirredat 25° C. for 20 hours. The reaction mixture was then concentrated, andthe resultant residue was diluted with water (100 mL) and neutralizedwith 6N HCl (30 mL). The mixture was extracted with DCM (200 mL), andthe organic layer was washed with water (150 mL) and brine. The organicsolution was then dried over anhydrous sodium sulfate and concentratedto provide B7-1 as a white solid. Yield: 2.8 g, 92%. ¹HNMR(CDCl3): δ7.7-7.76 (m, 1H), 7.6-7.65 (m, 1H), 6.8-6.98 (broad, 1H) and 3.14 (s,3H). Mass: (M−1) 195 calculated for C₈H₈N₂O₂S.

Step 2

A solution of B7-1 (2 g, 10.19 mmol) in a mixture of THF (133 mL) andacetic acid (250 mL) was charged to a Parr reactor. The contents of thereactor were then treated with 10% Pd/C (2 g) and hydrogenated at 60 Psihydrogen pressure and 25° C. for 4 hours. The reaction mixture wasfiltered through Celite® bed and concentrated. The resultant residue wasdiluted with toluene (20 mL) and concentrated. The resultant residue wasthen diluted with EtOAc (20 mL) and concentrated to provide 87 as whitesolid. Yield: 2 g, 98%. ¹HNMR (d₆-DMSO): δ 7.32-8.6 (broad, 4H),7.25-7.32 (m, 1H), 7.1-7.32 (m, 2H), 6.82 (t, 1H), 3.9 (s, 2H), 2.85 (s,3H) and 1.9 (s, 3H). Mass: (M+1) 201 calculated for C₈H₁₂N₂O₂S. HPLCPurity: 98.9%.

Preparation of N-(2-Aminomethyl-3-methyl-phenyl)-methanesulfonamideacetate (B8)

Step 1. Preparation ofN-(2-cyano-3-methyl-phenyl)-N-dimethanesulfonamide (B8-1)

A suspension of 2-amino-6-methyl benzonitrile (35 g, 265.5 mmol) inpyridine (600 rnL) was cooled to about 0° C. to −5° C. and slowlytreated with mesyl chloride (30 mL, 397.71 mmol) over 10 minutes. Thereaction mixture was allowed to warm to 26° C. and stirred at 25° C. for20 hours. The reaction mixture was concentrated and the resultantresidue was diluted with EtOAc (600 mL). The organic solution was thenwashed with water (100 mL), 2N HCl (100 mL), and saturated brine (100mL). The organic solution was then dried over anhydrous sodium sulfateand concentrated to provide B8-1 as a mixture of di- and mono-mesylatedproducts. Yield: 49 g. The product was used without further purificationto prepare 88-2 in the step described below.

Step 2. Preparation of N-(2-cyano-3-methyl-phenyl)-methanesulfonamide(B8-2)

A solution of B8-1 (35 g, 166.6 mmol) in THF (300 mL) was treated with40% aq. NaOH solution (300 mL) and BTEAC (1.84 g, 8.09 mmol) at 25° C.and stirred for 1 hour. The THF was removed under reduced pressure, andthe concentrated mixture was extracted with DCM (500 mL). The aqueouslayer was acidified with 2N HCl and extracted with DCM (250 mL). Thecombined organic layers were washed with water (100 mL) and brine (50mL). The organic solution was then dried over anhydrous sodium sulfateand concentrated. The resultant residue was purified by columnchromatography (60-120 mesh silica gel; 3% MeOH in CHCl₃ as elutingsolvent) to provide B8-2 as a brown solid. Yield: 24 g. ¹HNMR (d₆-DMSO):δ 9.98 (s, 1H), 7.6 (t, 1H), 7.26-7.4 (m, 2H), 3.1 (s, 3H), 2.5 (s, 3H).Mass: (M−1) 209 calculated for C₉H₁₀N₂O₂S.

Step 3

A solution of B8-2 (10 g, 47.6 mmol) in acetic acid (75 mL) and THF (250mL) was charged to a Parr reactor and treated with 10% Pd/C (6 g). Thereaction mixture was then hydrogenated at 50 Psi hydrogen pressure and25° C. for 16 hours. The reaction mixture was filtered through a Celite®bed and washed with ethanol (3×20 mL). The combined filtrates wereconcentrated, and the resultant residue was co-distilled with EtOAc (100mL). The resultant brown oil was dissolved in EtOAc (100 mL) and allowedto stand at 25° C. for 20 hours. The resultant white solids werecollected and dried to provide B8. Yield: 11 g. ¹HNMR (d₆-DMSO): δ7.65-8.65 (broad, 3H), 7.15 (d, 1H), 7.05 (t, 1H), 6.68 (d, 1H), 3.9 (s,2H), 2.8 (s, 3H), 2.26 (s, 3H) and 1.9 (s, 3H). Mass: (M+1) 215calculated for CO₉H₁₄N₂O₂S. HPLC Purity: 98.6%.

Preparation ofN-(2-Aminomethyl-3-methyl-phenyl)-N-methyl-methanesulfonamide acetate(B9)

Step 1. Preparation ofN-(2-cyano-3-methyl-phenyl)-N-methyl-methanesulfonamide (B9-1)

A solution of B8-1 (15 g, 71.42 mmol) in THF (150 mL) was treated with40% aq. NaOH (150 mL) and BTEAC (1.6 g, 7.14 mmol) at 25° C. and stirredfor 10 minutes. The reaction mixture was then cooled to 10° C. andtreated with methyl iodide (5.78 mL, 85.7 mmol). The reaction mixturewas allowed to warm to 25° C. and stirred at 25° C. for 20 hours. Thereaction mass was concentrated, and the resultant residue was dilutedwith DCM (600 mL). The organic solution was then washed with water (100mL) and brine (50 mL). The organic solution was dried over anhydroussodium sulfate and concentrated. The resultant residue was then purifiedby column chromatography (60-120 mesh silica gel; 2% MeOH in CHCl₃ aseluting solvent) to provide B9-1 as pale brown solid. Yield: 20 g, 98%.¹HNMR (d₆-DMSO): δ 7.65 (d, 1H), 7.56 (d, 1H), 7.45 (d, 1H), 3.25 (s,3H), 3.14 (s, 3H) and 2.5 (s, 3H). Mass: (M+1) 225 calculated forC₁₀H₁₂N₂O₂S.

Step 2

A solution of B9-1 (10 g, 47.6 mmol) in a mixture of THF (100 mL) andacetic acid (300 mL) was charged to a Parr reactor and treated with Pd/C(6 g). The contents of the reactor were then hydrogenated at 50 Psihydrogen pressure and 25° C. for 6 hours. The reaction mixture wasfiltered through a bed of Celite® and washed with ethanol (3×30 mL). Thecombined filtrates were concentrated, and the resultant residue wasco-distilled with EtOAc (100 mL). The resultant brown oil was taken intoEtOAc (100 mL) and stirred at 25° C. for 16 hours. The resultant whitesolids were collected, washed with EtOAc (2×25 mL), and dried to provideB9. Yield: 11.6 g, 89%. ¹HNMR (d₆-DMSO): δ 7.15-7.36 (m, 3H), 4.64-5.45(broad, 3H), 3.76 (d, 2H), 3.15 (s, 3H), 3.05 (s, 3H), 2.42 (s, 3H) and1.9 (s, 3H). Mass: (M+1) 229 calculated for C₁₀H₁₆N₂O₂S. HPLC Purity:97.4%.

Preparation of N-(2-Aminomethyl-5-methyl-phenyl)-methanesulfonamideacetate (B10)

Step 1. Preparation of 2-amino-4-methyl-benzonitrile (B10-1)

A solution of 4-methyl-2-nitrobenzonitrile (10 g, 61.72 mmol) in ethanol(200 mL) was charged to a Parr reactor and treated with 10% Pd/C (1 g).The contents of the reactor were then hydrogenated at 50 Psi hydrogenpressure 25° C. for 90 minutes. The reaction mixture was filteredthrough a Celite® bed and washed with ethanol. The combined filtrateswere the concentrated to provide B10-1. Yield: 8.5 g. ¹HNMR (CDCl₃): δ7.28 (s, 1H), 6.5-6.62 (m, 2H), 4.2-4.42 (broad, 2H) and 2.3 (s, 3H).Mass: (M−1) 132 calculated for C₈H₈N₂. The product was used withoutfurther purification to prepare B10-2 in the step described below.

Step 2. Preparation of N-(2-cyano-5-methyl-phenyl)-methanesulfonamideand N-(2-cyano-5-methyl-phenyl)-N-(methylsulfonyl)methanesulfonamide(B10-2)

A solution of B10-1 (8.5 g, 64.39 mmol) in pyridine (50 mL) was cooledto 0° C. and treated drop-wise with mesyl chloride (8.85 g, 77.22 mmol)over 15 minutes. The reaction mixture was allowed to warm to 25° C., andit was stirred at 25° C. for 20 hours. The reaction mixture was thenconcentrated, and the resultant residue acidified with 2N HCl (50 mL)and extracted with EtOAc (200 mL). The resultant organic layer waswashed with water (50 mL) and brine (50 mL), and dried over anhydroussodium sulfate. The organic solution was then concentrated to provideB10-2 as a mixture of both mono and di mesylated product. Yield: 9.2 g.The product was used without further purification to prepare B10-3 inthe step described below.

Step 3. Preparation of N-(2-cyano-5-methyl-phenyl)-methanesulfonamide(B10-3)

A solution of B10-2 (17 g, 80.95 mmol) in a mixture of THF (70 mL) and40% NaOH solution (70 mL) was treated with BTEAC (1.84 g, 8.09 mm) at25° C. and stirred at 25° C. for 20 hours. The THF was removed underreduced pressure, and the concentrated mixture was extracted with DCM(300 mL). The aqueous layer was acidified with 2N HCl and extracted withDCM (200 mL). The combined organic layers were washed with water (100mL) and brine (100 mL), and dried over anhydrous sodium sulfate. Theorganic solution was then concentrated, and the resultant residue waspurified by column chromatography (60-120 mesh silica gel; 30% EtOAc inDCM as eluting solvent) to provide B10-3 as a pale brown solid. Yield:16 g, 97%. ¹HNMR (d₆-DMSO): δ 7.9 (d, 1H), 7.7 (s, 1H), 7.55 (d, 1H),3.62 (s, 6H) and 2.45 (s, 3H). Mass: (M−1) 209 calculated forC₉H₁₀N₂O₂S.

Step 4

A solution of B10-3 (17 g, 80.95 mmol) in a mixture of THF (250 mL) andacetic acid (250 mL) was charged to a Parr reactor and treated with 10%Pd/C (8 g). at 25° C. The reaction mixture was then hydrogenated at 50Psi hydrogen pressure and 25° C. for 4 hours. The mixture was filteredthrough a Celite® bed and washed with ethanol (3×20 mL). The combinedfiltrates were concentrated and the resultant residue was azeotropedwith EtOAc (2×20 mL). The resultant brown-colored oil was taken intoEtOAc (50 mL) and allowed to stand at 25° C. for 20 hours. The resultantwhite solids were collected and dried to provide B10. Yield: 15.1 g,71.2%. ¹HNMR (d₆-DMSO): δ 7.62-8.2 (broad, 3H), 7.02-7.18 (m, 2H), 6.7(d, 1H), 3.85 (s, 2H), 2.88 (s, 3H), 2.25 (s, 3H) and 1.9 (s, 3H). Mass:(M+1) 215 calculated for C₉H₁₄N₂O₂S. HPLC Purity: 99.7%.

Preparation ofN-(2-Aminomethyl-5-methyl-phenyl)-N-methyl-methanesulfonamide acetate(B11)

Step 1. Preparation ofN-(2-cyano-5-methyl-phenyl)-N-methyl-methanesulfonamide (B11-1)

A solution of B10-2 (10 g, 47.61 mmol) in a mixture of THF (100 mL) and40% aq. NaOH solution (100 mL) at 25° C. was treated with BTEAC (1.1 g,4.7 mmol) and methyl iodide (8.78 g, 61.89 mmol). The reaction mixturewas then stirred at 25° C. for 20 hours. The THF was removed underreduced pressure, and the concentrated mixture was extracted with DCM(300 mL). The organic layer was washed with water (100 mL) and brine (50mL), and dried over anhydrous sodium sulfate. The organic solution wasthen concentrated, and the resultant residue was purified by columnchromatography (60-120 mesh silica gel; 10% EtOAc in CHCl₃ as elutingsolvent) to provide B81-1 as a brown solid. Yield: 10.3 g, 96%. ¹HNMR(CDCl₃): δ 7.62 (d, 1H), 7.38 (s, 1H), 3.38 (s, 3H), 3.1 (s, 3H) and2.45 (s, 3H). Mass: (M−1) 223 calculated for C₁₀H₁₂N₂O₂S.

Step 2

A solution of B11-1 (4 g, 17.85 mmol) in acetic acid (150 mL) wascharged to a Parr reactor and treated with Pd/C (2 g). The contents ofthe reactor were then hydrogenated at 50 Psi hydrogen pressure and 25°C. for 6 hours. The reaction mixture was filtered through a Celite® bedand washed with ethanol (2×20 mL). The combined filtrates wereconcentrated, and the resultant brown solid was azeotroped with EtOAc(3×25 mL). The resultant solid was taken into EtOAc (25 mL) at stirredat 25° C. for 20 hours. The resultant solids were collected and driedunder reduced pressure to provide B11. Yield: 2.7 g, 53%. ¹HNMR(d₆-DMSO): δ 7.45 (d, 1H), 7.3 (s, 1H), 7.2 (d, 1H), 5.04-5.7 (broad,2H), 3.75-3.92 (broad, 2H), 3.15 (s, 3H), 3.05 (s, 3H), 2.3 (s, 3H) and1.9 (s, 2H). Mass: (M+1) 229 calculated for C₁₀H₁₆N₂O₂S. HPLC Purity:97.7%.

Preparation ofN-(2-Aminomethyl-6-methyl-phenyl)-N-methyl-methanesulfonamidetrifluoroacetate (B12)

Step 1. Preparation of Potassium di-tert-butyl iminodicarboxylate(B12-1)

A solution of di-tert-butyl iminodicarboxylate (56 g, 258 mmol) inethanol (200 mL) was cooled to 15° C. and treated over 30 minutes with asolution of KOH (17 g) in ethanol (150 mL). The reaction mixture wasallowed to warm to 25° C., and it was stirred at 25° C. for 4 hours. Thereaction mixture was then concentrated, and the resultant residue wasdiluted with diethyl ether (300 mL) and stirred for 3 hours. Theresultant solids were collected and immediately dried under reducedpressure to provide B12-1 as a white crystalline solid. Yield: 57 g,82%. ¹HNMR (d₆-DMSO): δ 1.35 (s, 18H). Mass: (M−1) 216 calculated forC₁₀H₁₉NO₄.

Step 2. Preparation of 1-chloromethyl-3-methyl-2-nitro-benzene (B12-2)

A solution of 3-(methyl-2-nitro-phenyl)-methanol (12 g, 71.78 mmol) inDCM (500 mL) was cooled to −5° C. and treated with dimethylaminopyridine(DMAP) (11.4 g, 93.3 mm) followed by treatment with a solution of tosylchloride (17.79 g, 93.3 mmol) in DCM. The reaction mixture was stirredat −5° C. for 30 minutes. The reaction mixture was then allowed to warmto 25° C., and it was stirred at 25° C. for 20 hours. The reactionmixture was diluted with DCM (100 mL) and washed with 1N HCl (2×50 mL),saturated NaHCO₃ (2×25 mL), and brine. The organic solution was thendried over anhydrous MgSO₄ and concentrated. The resultant residue waspurified by column chromatography (silica gel column; 15% EtOAc inhexane as eluting solvent) to provide B12-2 as a pale greenish-yellowoil. Yield: 14 g, 89%. ¹HNMR (CDCl₃): δ 7.35-7.46 (m, 2H), 7.26-7.35 (m,1H), 4.6 (s, 2H) and 2.36 (s, 3H).

Step 3. Preparation of 3-methyl-2-nitro-benzyl di-tert-butyliminodicarboxylate (B12-3)

A solution of B12-2 (14 g, 75.6 mmol) in N-methylpyrrolidinone (NMP)(135 mL) was cooled to −5° C. and treated with B12-1 (29.7 g, 116.4mmol) over 20 minutes. The mixture was then heated at 50° C. for 4 hour.The reaction mixture was diluted with water (150 mL) and extracted withEtOAc (4×250 ml.). The combined organic layers were washed with water(300 mL) and brine. The organic solution was then dried over anhydrousMgSO₄ and concentrated. The resultant residue was purified by columnchromatography (silica gel; 20% EtOAc in hexane as eluting solvent) toprovide B12-3 as an-off white solid. Yield: 21 g, 76%. ¹HNMR (CDCl₃): δ7.35 (t, 1H), 7.1-7.25 (m, 211H), 4.76 (s, 2H), 2.3 (s, 3H) and 1.42 (s,18H).

Step 4. Preparation of 2-amino-3-methyl benzyl di-tert-butyliminodicarboxylate (B12-4)

A solution of B12-3 (20 g, 54.64 mmol) in ethanol (500 mL) was chargedto a Parr reactor and treated with 10% Pd/C (7 g). The contents of thereactor were then hydrogenated at 55 Psi hydrogen pressure and 25° C.for 5 hours. The reaction mixture was filtered through a Celite® bed andconcentrated to provide B12-4 as a pale greenish-yellow oil (19 g).¹HNMR (CDCl₃): δ 7.1 (d, 1H), 6.96 (d, 1H), 6.6 (t, 1H), 4.7 (s, 2H),4.3-4.5 (broad, 2H), 2.15 (s, 3H) and 1.45 (s, 18H).

Step 5. Preparation of di-BOC 3-methyl-2-(methylsulfonamido)benzylamine(B12-5)

A solution of B12-4 (20 g, 59.6 mmol) in pyridine (150 mL) was cooled to0° C. and treated over 25 minutes with mesyl chloride (6.15 mL, 79.4mmol). The mixture was allowed to warm to 25° C., and it was stirred at25° C. for 20 hours. The reaction mixture was diluted with EtOAc (300mL) and washed with 1N HCl solution. The aqueous layer was collected andextracted with EtOAc (100 mL). The combined organic layers were washedwith brine and dried over anhydrous MgSO₄. The organic solution was thenconcentrated, and the resultant residue was taken into petroleum etherand stirred for 1 hour. The resultant solids were collected and driedunder reduced pressure to provide B12-5 as an off white solid. Yield: 22g, 89%. ¹HNMR (CDCl₃): δ 7.9 (s, 1H), 7.35 (d, 1H), 7.05-7.25 (m, 2H),4.9 (s, 2H), 3.1 (s, 3H), 2.45 (s, 3H) and 1.45 (s, 18H). Mass: (M−1)413 calculated for C₁₉H₃₀N₂O₆S.

Step 6. Preparation of di-BOC3-methyl-2-(N-methylmethan-2-ylsulfonamido)benzylamine (B12-6)

A solution of B12-5 (22 g, 53.14 mmol) in THF (58.6 mL) was cooled to15° C. and treated with 40% aq NaOH solution (58.6 mL) followed by BTEAC(1.25 g, 5.5 mm). The mixture was stirred for 15 minutes and the treatedover 20 minutes with methyl iodide (4.2 mL, 67.4 mmol). The reactionmixture was allowed to warm to 25° C., and it was stirred at 25° C. for20 hours. The reaction mixture was then diluted with water (300 mL) andextracted with DCM (3×200 mL). The combined organic layers were washedwith water (3×400 mL) and brine, dried over anhydrous MgSO₄, andconcentrated. The resultant residue was dissolved in petroleum ether ina glass flask, and the wall of the flask was scratched to induce solidsformation. The resultant solids were collected and dried to provideB12-6 as a pale yellow solid. Yield: 20 g, 88%. ¹HNMR (CDCl₃): δ7.1-7.25 (m, 2H), 7.04 (d, 1H), 5.05 (d, 1H), 4.8 (d, 1H), 3.25 (s, 3H),3.1 (s, 3H), 2.36 (s, 3H) and 1.45 (s, 18H).

Step 7

A solution of B12-6 (13 g, 30.3 mmol) in DCM (35 mL) was cooled to 0° C.and treated with trifluoroacetic acid (TFA) (70 mL). The reactionmixture was allowed to warm to 25° C., and it was stirred at 25° C. for2 hours. The reaction mixture was concentrated, and the resultantresidue was azeotroped with EtOAc (2×100 mL). The resultant residue wasdiluted with a mixture of DCM and pentane (1:1) in a glass flask, andthe wall of the flask was scratched. The contents of the flask werestirred for 1 hour, and the resultant precipitate was collected anddried to provide B12 as an off white solid. Yield: 9 g, 87%. ¹HNMR(d₆-DMSO): δ 8.3-8.45 (broad, 2H), 7.38-7.5 (m, 3H), 4.2 (s, 2H), 3.14(s, 6H), and 2.44 (s, 3H). Mass: (M+1) 229 calculated for C₁₀H₁₆N₂O₂S.HPLC Purity: 97.5%.

Preparation ofN-(2-Aminomethyl-4-methyl-phenyl-N-methyl-methanesulfonamidetrifluoroacetate (B13)

Step 1. Preparation of di-BOC-5-methyl-2-nitrobenzylamine (B13-1)

A solution of 2-chloromethyl-4-methyl-1-nitro-benzene (20 g, 107.5 mmol)in NMP (140 mL) was cooled to 0° C. and treated over 30 minutes withpotassium di-tert-butyl iminodicarboxylate (40 g, 156 mmol). Thereaction mixture was allowed to warm to 25° C., and it was stirred at25° C. for 20 hours. The reaction mixture was then diluted with water(150 mL) and extracted with EtOAc (2×500 mL). The resultant organiclayer was washed with water (250 mL) and brine, and dried over anhydrousMgSO₄ The organic solution was then concentrated, and the resultantresidue was purified by column chromatography (silica gel; 20% EtOAc inhexane as eluting solvent) to provide B13-1 as a pale yellow solid.Yield: 29 g, 73%. ¹HNMR (CDCl₃): δ 7.98 (d, 1H), 7.2 (d, 1H), 7.1 (s,1H), 5.15 (s, 2H), 2.4 (s, 3H) and 1.44 (s, 18H).

Step 2. Preparation of di-BOC 2-amino-5-methylbenzylamine (B13-2)

A solution of B13-1 (29 g, 79.23 mmol) in ethanol (500 mL) was chargedto a Parr reactor and treated with Pd/C (9 g). The contents of thereactor were then hydrogenated 55 Psi hydrogen pressure and 25° C. for 2hours. The reaction mixture was filtered through a Celite® bed andconcentrated to provide B13-2 as an oil. Yield: 26 g. ¹HNMR (CDCl₃): δ7.02 (s, 1H), 6.85 (d, 1H), 6.55 (d, 1H) 4.7 (s, 2H), 4.02-4.38 (broad,2H), 2.22 (s, 3H) and 1.46 (s, 18H).

Step 3. Preparation of di-BOC 5-methyl-2-(methylsulfonamido)benzylamine(B13-3)

A solution of B13-2 (26 g, 77.38 mmol) in pyridine (165 mL) was cooledto 0° C. and treated over 20 minutes with mesyl chloride (12.18 g, 106.4mmol) was added over a period of 20 min. The mixture was allowed to warmto 25° C., and it was stirred at 25° C. for 20 hours. The reactionmixture was then diluted with EtOAc (350 mL) and washed with 1N HClsolution (2×250 mL). The resultant organic layer was washed with brine,dried over anhydrous MgSO₄, and concentrated. The resultant residue wastreated with petroleum ether and stirred at 25° C. for 1 hour. Theresultant solids were then collected and dried under reduced pressure toprovide B13-3 as a pale yellow solid. Yield: 23 g, 71%. ¹HNMR (CDCl₃): δ8.7 (s, 1H), 7.45 (d, 1H), 7.1 (d, 1H), 4.72 (s, 2H), 2.96 (s, 3H), 2.3(s, 3H) and 1.46 (s, 18H). Mass: (M−1) 413 calculated for C₁₉H₃₀N₂O₆S.

Step 4. Preparation of di-BOC5-methyl-2-(N-methylmethan-2-ylsulfonamido)benzylamine (B13-4)

A solution of B13-3 (22 g, 53.14 mmol) in THF (70 mL) was cooled to 0°C. and treated with 40% aq. NaOH solution (70 mL) followed by BTEAC (1.5g, 6.6 mmol). After 15 minutes the mixture was treated with methyliodide (9.51 g, 67.4 mmol) over a period of 20 minutes. The reactionmixture was allowed to warm to 25° C., and it was stirred at 25° C. for20 hours. The reaction mixture was then diluted with DCM (800 mL). Theorganic layer was collected and washed with water (2×200 mL) and brine,and dried over anhydrous MgSO₄. The organic solution was concentrated,and the resultant residue was triturated with petroleum ether to provideB13-4 as a pale yellow solid. Yield: 20 g, 88%. ¹HNMR (CDCl₃): δ 7.0-7.4(m, 3H), 4.85-5.1 (d, 2H), 3.25 (s, 3H), 2.92 (s, 3H), 2.35 (s, 3H) and1.45 (s, 18H).

Step 5

A solution of B13-4 (15 g, 35.04 mmol) in DCM (45 mL) was cooled to 0°C. and treated over 30 minutes with TFA (90 mL). The mixture was thenallowed to warm to 25° C. After 3 hours the mixture was concentrated,and the resultant residue was azeotroped with EtOAc (2×200 mL). Theresultant residue was diluted with a mixture of DCM and ether (8:2) andstirred for 1 hour. The resultant precipitate was collected and driedunder reduced pressure to provide B13 as an off-white solid. Yield: 12g, 98%. ¹HNMR (d₆-DMSO): δ 7.98-8.2 (broad, 2H), 7.5 (d, 1H), 7.4 (s,1H), 7.3 (d, 1H), 3.96-4.28 (broad, 2H), 3.2 (s, 3H), 3.05 (s, 3H) and2.35 (s, 3H). Mass: (M+1) 229 calculated for C₁₀H₁₆N₂O₂S.

Preparation ofN-(3-Aminomethyl-6-methyl-pyridin-2-yl-N-methyl-methanesulfonamideacetate (B14)

Step 1. Preparation ofN-(3-cyano-6-methyl-pyridin-2-yl)-N-methyl-methanesulfonamide (B14-1)

A solution of 2-chloro-6-methyl-nicotinonitrile (20 g, 131.5 mmol) inacetonitrile (300 mL) at 25° C. was treated with HN(CH₃)SO₂Me (13.1 mL,124.1 mmol) and Cs₂CO₃ (60 g, 184.0 mm). The reaction mixture was thenstirred at 80° C. for 15 hours. The reaction mixture was allowed to coolto 25° C. and filtered. The resultant filtrate was concentrated anddiluted with EtOAc (600 mL). The organic solution was then washed withwater (2×250 mL) and brine, and dried over anhydrous sodium sulfate. Theorganic solution was then concentrated, and the resultant residue wasrecrystallized with ether to provide B14-1 as an off white solid. Yield:18.5 g, 62.5%. ¹HNMR(CDCl₃): δ 7.9 (d, 1H), 7.16-7.26 (m, 1H), 3.28 (s,3H), 3.24 (s, 3H) and 2.22 (s, 3H). Mass: (M+1) 226 calculated forC₉H₁₁N₃O₂S.

Step 2

A solution B14-1 (10 g, 44.4 mmol) in a mixture of THF (100 mL) andacetic acid (900 mL) was charged to a Parr reactor and treated with 10%Pd/C (9 g, 84.9 mmol). The contents of the reactor were thenhydrogenated at 55 Psi hydrogen pressure and 40° C. for 4 hours. Thereaction mixture was then filtered through a Celite® bed andconcentrated. The resultant residue was diluted with EtOAc (100 mL) andstirred for 3 hours. The resultant solids were collected and dried underreduced pressure to provide B14 as an off-white solid. Yield: 10 g, 98%.¹HNMR (d₆-DMSO): δ 7.9 (d, 1H), 7.3 (d, 1H), 7.0-7.25 (broad, 2H), 3.82(s, 2H), 3.06-3.18 (d, 5H), 2.45 (s, 3H) and 1.82-1.96 (m, 5H). Mass:(M+1) 230 calculated for C₉H₁₅N₃O₂S. HPLC Purity: 98.1%.

Preparation ofN-(3-Aminomethyl-5-methyl-pyridin-2-yl)-N-methyl-methanesulfonamideacetate (B15)

Step 1. Preparation of 5-methyl-nicotinic Acid (B15-1)

A solution of 3,5 lutidine (100 g, 934.57 mmol) in water at 25° C. wastreated portion-wise over 5 hours with KMnO₄ (221.1 g, 1401.86 mmol).The reaction mixture was then heated at 45° C. for about 20 hours. Thereaction mixture was filtered and washed with water. The resultantfiltrates were concentrated, and the resultant residue was diluted withethanol (3×500 mL), boiled, and filtered. The filtrate was thenconcentrated under reduced pressure to provide B15-1 as a white solid.Yield: 76 g, 59.4%. ¹HNMR (D₂O): δ 8.6-8.7 (s, 1H), 8.3-8.4 (m, 1H),7.92 (s, 1H) and 2.3 (s, 3H). Mass: (M+1) 138 calculated for C₇H₇NO₂.

Step 2. Preparation of 5-methyl-nicotinamide (B15-2)

A suspension of B15-1 (70 g, 510 mmol) in thionyl chloride (350 mL) washeated at 80° C. for 20 hours. The resultant clear solution obtained wasallowed to cool to 25° C. and concentrated. The resultant residue wasdiluted with 1,2 dichloroethane (1.5 L), cooled to −5° C., and treatedwith NH₃ gas via bubbler until the mixture was saturated. The mixturewas allowed to warm to 25° C., stirred for 3 hours, and concentrated.The resultant brown solid was taken in EtOAc (3×800 mL), refluxed for 20min, and filtered. The resultant filtrate was then concentrated toprovide B15-2 as a brown solid. Yield: 52 g, 75%. ¹HNMR (d₆-DMSO): δ8.85-8.9 (s, 1H), 8.55 (s, 1H), 8.05-8.18 (m, 1H), 8.02 (s, 1H),7.48-7.65 (s, 1H) and 2.35 (s, 3H). Mass: (M+1) 137 calculated forC₇H₈N₂O.

Step 3. Preparation of 1-Hydroxy-5-methyl-nicotinamide (B15-3)

A solution of B15-2 (35 g) in acetic acid (200 mL) was cooled to 10° C.and treated over 10 minutes with H₂O₂ (40% solution in water, 200 mL).The reaction mixture was allowed to warm to 25° C. and then heated at80° C. for 20 hours. The reaction mixture was cooled to 0° C., treatedwith 20% sodium sulfite solution (200 mL) and basified with 35% NH₄OH(200 mL). The mixture was then allowed to warm to 25° C. and stirred foran additional 2 hours. The resultant solids were collected and driedunder reduced pressure to provide B15-3 as a white solid. Yield: 30.1 g.¹HNMR (d₆-DMSO): δ 8.45 (s, 1H), 8.3 (s, 1H), 7.6 (s, 1H), 4.42-4.7(broad m, 2H), 2.3 (s, 3H). Mass: (M−1) 153 calculated for C₇H₁₀N₂O₂.

Step 4. Preparation of 2-chloro-5-methyl-nicotinonitrile (B15-4)

Neat POCl₃ (120 mL) was cooled to about 10° C. and treated portion-wiseover 10 minutes with B15-3. The reaction mixture was then heated at 60°C. for 2 hours. The reaction mixture was concentrated, cooled to about10° C., basified with saturated Na₂CO₃, and extracted with EtOAc (3×100mL). The combined organic layers were washed with water (50 mL), andbrine (50 mL), and dried over anhydrous sodium sulfate. The organicsolution was then concentrated, and the resultant residue was purifiedby column chromatography (silica gel; 35% EtOAc in hexane as elutingsolvent) to provide to B15-4 as a white solid. Yield: 3.5 g, 68%. ¹HNMR(d₆-DMSO): δ 8.42 (s, 1H), 7.82 (s, 1H) and 2.4 (s, 3H). Mass: (M+1) 153calculated for C₇H₅ClN₂.

Step 5. Preparation ofN-(3-cyano-5-methyl-pyridin-2-yl)-N-methyl-methanesulfonamide (B15-5)

A suspension of B15-4 (16 g, 0.1049 mmol) in acetonitrile (150 mL) at25° C. was treated with Cs₂CO₃ (51.3 g, 0.157 mmol) and N-methyl methanesulphonamide (12.5 g, 0.115 mmol). The reaction mixture was then heatedat 80° C. for 20 hours. The reaction mixture was filtered through aCelite® bed and washed with acetonitrile (3×50 mL). The combinedfiltrates were concentrated, and the resultant residue was diluted withEtOAc (500 mL) and washed with water (3×100 mL). The resultant organiclayer was washed with brine (100 mL), dried over anhydrous sodiumsulfate, and concentrated. The resultant residue was purified by columnchromatography (silica gel; 40% EtOAc in hexane as eluting solvent) toprovide B15-5 as pale yellow solid. Yield: 15.1 g, 62.8%. ¹HNMR(d₆-DMSO): δ 8.65 (s, 1H), 8.3 (s, 1H), 3 3.22-3.26 (s, 3H), 0.15-3.22(s, 3H) and 2.36 (s, 3H). Mass: (M+1) 226 calculated for C₉H₁₁N₃O₂S.

Step 6

A solution of B15-5 (15 g) in a mixture of acetic acid (200 mL) and THF(200 mL) was charged to a Parr reactor and treated with Pd/C (4 g). Thecontents of the reactor were then hydrogenated at 50 Psi hydrogenpressure and 25° C. for 5 hours. The mixture was filtered through aCelite® bed and washed with ethanol (50 mL). The filtrate wasconcentrated under reduced pressure, and the resultant residue waspurified by column chromatography (silica gel; 5% MeOH in CHCl₃ aseluting solvent) to provide B15 as a reddish brown solid. Yield: 12.3 g,98%. IR (cm⁻¹): 3450, 3264, 2937, 2161, 1706, 1633, 1548, 1413, 1321 and1151. ¹HNMR (d₆-DMSO): δ 8.3 (s, 1H), 7.9 (s, 1H), 7.02-7.25 (broad s,2H), 3.92 (s, 2H), 3.15 (d, 6H), 2.4 (s, 3H), 1.92 (s, 3H). Mass: (M+1)C₉H₁₅N₃O₂S. (Note: Few drops of triethylamine was added to the mobilephase during the process of silica gel column purification.)

Preparation ofN-(3-Aminomethyl-4-methyl-pyridin-2-yl)-N-methyl-methanesulfonamide(B16)

Step 1. Preparation ofN-(3-cyano-4-methyl-pyridin-2-yl)-N-methyl-methanesulfonamide (B16-1)

A suspension of 2-chloro-4-methyl-nicotinonitrile (4 g, 26.2 mmol) (seeWO 02/30901), N-methyl methane sulphonamide (3.43 g, 31.4 mmol) andCsCO₃ (12 g, 36.7 mmol) in acetonitrile (40 mL) was heated at 60° C. for20 hours. The reaction mixture was filtered through a Celite® bed andwashed with acetonitrile (40 mL). The combined filtrates wereconcentrated, and the resultant residue was diluted with EtOAc (100 mL).The organic solution was washed with water (100 mL) and brine (50 mL),and dried over anhydrous sodium sulfate. The organic solution was thenconcentrated, and the resultant residue was stirred in methanol. Theresultant solids were collected and dried under reduced pressure toprovide B16-1 as a white solid. Yield: 1.6 g, 26%. ¹HNMR (CDCl₃): δ 8.46(d, 1H), 7.25 (m, 1H), 3.26 (s, 3H), 3.18 (s, 3H) and 2.6 (s, 3H). Mass:(M+1) 226 calculated for C₉H₁₁N₃O₂S.

Step 2

A solution of B16-1 (5 g, 22.1 mmol) in 2N ethanolic ammonia (250 mL)was charged to a Parr reactor and treated with 10% Pd/C (5 g, 47 mm).The contents of the reactor were then hydrogenated at 60 Psi hydrogenpressure and 25° C. for 6 hours. The reaction mixture was filteredthrough a Celite® bed and washed with ethanol (50 mL). The combinedfiltrates were concentrated, and the resultant oily residue wastriturated with diethyl ether (20 mL). The resultant white solids werecollected and dried to provide B16 as a white solid. Yield: 5 g, 90%.¹HNMR (d₆-DMSO): δ 8.46 (d, 1H), 8.2-8.38 (broad s, 2H), 7.42 (d, 1H),4.55-4.9 (broad s, 4H), 4.15-4.3 (broad s, 2H), 325 (s, 3H), 3.1 (s, 3H)and 2.5 (s, 3H). Mass: (M+1) 230 calculated for C₉H₁₅N₃O₂S. HPLC Purity:95.03%.

Preparation ofN-(5-aminomethyl-2-methyl-pyfridin-4-yl)-N-methyl-methansulfonamideacetate (B17)

Step 1. Preparation of 2,4-dihydroxy-6-methyl-nicotinic acid ethyl ester(B17-1)

Sodium metal pieces (33 g, 1434 mmol) were slowly added to dry ethanol(800 mL) at 25° C. and stirred until all the sodium pieces had reacted.The resultant suspension was then treated over 15 minutes with malonicacid diethyl ester (140 g, 875 mmol) followed by treatment over 15minutes with ethyl-3-aminocrotonate (110 g, 850 mmol). The reactionmixture was then heated at 110° C. for 20 hours and concentrated. Theresultant residue was cooled to 15° C., dissolved in water (800 mL), andstirred for 15 minutes. The mixture was neutralized with a mixture ofAcOH:H₂O (1:1) until a pH of 6-7 was achieved. The mixture was thenstirred an addition 20 minutes. The resultant solids were collected,washed with petroleum ether (300 mL), and dried under reduced pressureto provide B17-1 as an off-white solid. Yield: 60.3 g, 35%. ¹HNMR(d₆-DMSO): δ 12.6 (s, 1H), 11.38 (s, 1H), 5.8 (s, 1H), 4.25 (q, 2H),2.14 (s, 3H) and 1.25 (t, 3H). Mass: (M+1) 198 calculated for C₉H₁₁NO₄.

Step 2. Preparation of 2,4-dichloro-6-methyl-nicotinic acid ethyl ester(B17-2)

A suspension of 817-1 (36 g, 182.2 mmol) in N,N-bis(2-hydroxyethyl)2-propanolamine (DEIPA) (36 mL) was cooled to 0° C. and slowly treatedwith POCl₃ (250 mL). The resultant clear solution was allowed to warm to25° C. and then heated at 15° C. for 20 hours. The reaction mixture wasconcentrated, and the resultant residue was poured into crushed ice. Thechilled mixture was then basified with saturated Na₂CO₃ until a pH of 8was achieved. The organic layer was collected, and the aqueous layer wasextracted with EtOAc (3×500 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, and concentrated. Theresultant residue was purified by chromatography (silica gel; 2% EtOAcin petroleum ether as eluting solvent) to provide B17-2 as a pale yellowsolid. Yield: 24 g, 55%. ¹HNMR (d₆-DMSO): δ 7.2 (s, 1H), 4.45 (q, 2H),2.52 (s, 3H) and 1.42 (t, 3H). Mass: (M+1) 236 calculated forC₉H₉Cl₂NO₂.

Step 3. Preparation of 2-chloro-4-methoxy-6-methyl-nicotinic acid ethylester (B17-3)

A solution of B17-2 (30 g, 128.2 mmol) in methanol (102 mL) was cooledto 000° C. and treated portion-wise over 30 minutes with NaOMe (8.5 g,157.4 mmol). The reaction mixture was then heated at 60° C. for 5 hours.The reaction mixture was cooled to 25° C., filtered, and concentrated.The resultant residue was diluted with DCM (350 mL), filtered through aCelite® bed, and washed with DCM. The combined filtrates wereconcentrated, and the resultant residue was purified by chromatography(silica gel; 6% EtOAc in petroleum ether as eluting solvent) to provideB17-3 as a pale yellow solid. Yield: 20.62 g, 70%. ¹HNMR(CDCl₃): δ 6.66(s, 1H), 4.4 (q, 2H), 3.95 (s, 1H), 3.92 (s, 3H), 2.52 (s, 3H) and 1.38(t, 3H). Mass: (M+1) 230 calculated C₁₀H₁₂ClNO₃.

Step 4. Preparation of 4-methoxy-6-methyl-nicotinic acid ethyl ester(B17-4)

A mixture of 817-3 (27 g, 117.3 mmol) and potassium acetate (11.0 g, 112mmol) in isopropanol (IPA) (500 mL) was charged to a Parr reactor andtreated with Pd/C (9.5 g, 70.15 mmol). The contents of the reactor werethen hydrogenated at 55 Psi hydrogen pressure and 25° C. for 4 hours.The mixture was filtered through a Celite® bed and concentrated. Theresultant residue was purified by chromatography (silica gel; 8% EtOAcin petroleum ether as eluting solvent) to provide B17-4 as a greenviscous liquid. Yield: 23 g, 90%. ¹HNMR(CDCl₃): δ 8.84 (s, 1H), 6.75 (s,1H), 4.35 (q, 2H), 3.98 (s, 3H), 2.6 (s, 3H) and 1.4 (t, 3H). Mass:(M+1) 196 calculated for C₁₀H₁₃NO₃.

Step 5. Preparation of 6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylicacid hydrochloride (B17-5)

A suspension of B17-4 (50 g, 256 mmol) in concentrated HCl (600 mL) washeated at 110° C. for 20 hours. The reaction mixture was thenconcentrated, and the resultant residue was washed in this order withethanol (150 mL), DCM (2×300 mL), and a mixture of DCM:Et₂O (1:1). Theresultant solids were collected and dried to provide B17-5 as anoff-white solid. Yield: 40 g. IR (cm⁻¹): 3449, 3095, 2890, 1674, 1647,1565, 1470, 1428, 1345, 1257, 1186 and 1028. ¹HNMR (d₆-DMSO): δ11.4-12.7 (b, 2H), 8.45 (s, 1H), 6.64 (s, 1H) and 2.4 (s, 3H). Mass:(M+1) 154 calculated for C₇H₇NO₃.

Step 6. Preparation of 6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylicacid methyl ester (B17-6)

A solution of B17-5 (40 g, 261.4 mmol) in methanol (600 mL) was cooledto 0° C. and treated drop-wise over 20 minutes with SOCl₂ (100 mL). Thereaction mixture was allowed to warm to 25° C., heated at 70° C. for 20hours, and concentrated. The resultant residue was washed with ethanol(100 mL), filtered and dried to provide B17-6 as a gummy solid. Yield:40 g. ¹HNMR (CDCl₃): δ 8.8 (s, 1H), 6.7 (s, 1H), 3.9 (s, 3H) and 2.45(s, 3H). Mass: (M+1) 168 calculated for C₈H₉NO₃. The product was used inthe preparation of B17-7 below without further purification.

Step 7. Preparation of 6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylicacid amide (B17-7)

A suspension of B17-6 (40 g, 239.5 mmol) in aqueous NH₃ (800 mL) washeated at 50° C. for 20 hours. The reaction mass was then concentrated,and the resultant residue was washed with a mixture of diethyl ether:DCM(8:2) (300 mL). The resultant solids were collected and dried underreduced pressure to provide B17-7 as an off-white solid. Yield. 40 g.¹HNMR (d₆-DMSO): δ 12.1 (b, 1H), 9.4 (s, 1H), 8.3 (s, 1H), 7.4 (s, 1H),6.25 (s, 1H) and 2.25 (S, 3H). Mass: (M+1) 153 calculated for C₇H₈N₂O₂.

Step 8. Preparation of 4-Chloro-6-methyl-nicotinonitrile (B17-8)

A suspension of B17-7 (20 g, 131.5 mmol) in POCl₃ (62 mL, 580 mmol) washeated at 110° C. for 15 minutes. The mixture was allowed to cool to 25°C. and treated portion-wise over 20 minutes with PCl₅ (38.12 g, 183.4mmol). The mixture was then heated at 110° C. for 1 hour andconcentrated. The resultant residue was diluted with EtOAc (100 mL),cooled to 10° C., and quenched with aqueous Na₂CO₃ (200 mL). The mixturewas then extracted with EtOAc (3×250 mL), and the combined organiclayers were washed with brine, dried over anhydrous sodium sulfate, andconcentrated. The resultant residue was purified by chromatography(silica gel; 4-5% EtOAc in petroleum ether as eluting solvent) toprovide B17-8 as an off-white puffy solid. Yield: 7.5 g, 37%. ¹HNMR(CDCl₃): δ 8.75 (s, 1H), 7.38 (s, 1H), 2.65 (s, 3H). Mass: (M+1) 153calculated for C₇H₅ClN₂.

Step 9. Preparation ofN-(5-Cyano-2-methyl-pyridin-4-yl)-N-methyl-methanesulfonamide (B17-9)

A solution of B17-8 (7 g, 46.8 mmol) in acetonitrile (165 mL) at 25° C.was treated sequentially with Cs₂CO₃ (19 g, 58.2 mmol) and HN(Me)SO₂Me(8.9 mL, 95 mmol). The mixture was heated at 60° C. for 20 hours andconcentrated. The resultant residue was diluted with EtOAc (300 mL) andwater (100 mL), and stirred for 10 minutes. The organic layer wascollected, and the aqueous layer was extracted with EtOAc (2×100 mL).The combined organic layers were washed with brine, dried over MgSO₄,and concentrated. The resultant residue was purified by chromatography(silica gel; DCM as eluting solvent) to provide B17-9 as a solid. Yield:9 g, 87%. ¹HNMR (CDCl₃): δ 8.8 (s, 1H), 7.3 (d, 1H), 3.4 (s, 3H), 3.18(s, 3H) and 2.65 (s, 3H). Mass: (M+1) 226 calculated for C₉H₁₁N₃O₂S.

Step 10

A solution of B17-9 (7.5 g, 33.3 mmol) in EtOH—NH₃ (300 mL) was chargedto a Parr reactor and treated with Pd/C (5 g). The contents of thereactor were hydrogenated at 60 Psi hydrogen pressure and 25° C. for 4hours. The mixture was filtered through a Celite® bed and concentrated.The resultant residue was diluted with EtOAc:acetic acid (1.1 eq.) andconcentrated. The resultant gummy orange-colored liquid was then dilutedwith a mixture of ether and EtOAc in a glass flask, and the wall of theflaks was scratched. The resultant solids were collected to provide B17as an off-white solid. Yield: 4.4 g, 42%. IR (cm⁻¹): 3484, 3343, 3166,2975, 1644, 1601, 1560, 1505, 1412, 1313, 1136 and 1058. ¹HNMR(d_(b)-DMSO): δ 8.62 (s, 1H), 7.4 (s, 1H), 4.7-5.3 (broad, 3H), 3.82 (s,2H), 3.14 (d, 2H), 2.45 (s, 3H) and 1.9 (s, 3H). Mass: (M+1) 230calculated 230 for C₉H₁₅N₃O₂S.

Preparation ofN-(3-Aminomethyl-4-methyl-phenyl)-N-methyl-methanesulfonamide acetate(B18)

Step 1. Preparation of 5-amino-2-methyl-benzonitrile (B18-1)

A stirred suspension of 2-methyl-5-nitro benzonitrile (20 g, 123.45mmol) in a mixture of dioxane (640 mL), ethanol (480 mL) and water (160mL) at 25° C. was treated with NH₄Cl (26.4 g, 493.8 mmol) followed bytreatment with iron powder (34.4 g, 617.2 mmol). The mixture was thenheated at 80° C. for 16 hours. The mixture was filtered through aCelite® bed and concentrated. The resultant residue was diluted withEtOAc (600 mL), washed with water (150 mL) and brine (100 mL), and driedover anhydrous sodium sulfate. The organic solution was thenconcentrated to provide B18-1 as an orange solid. Yield: 18.2 g.¹HNMR(CDCl₃): δ 7.08 (d, 1H), 6.84-6.9 (m, 1H), 6.75-6.82 (m, 1H),3.65-3.82 (m, 2H) and 2.4 (s, 3H). Mass: (M+1) 133 calculated forC₈H₈N₂. The product was used below to prepare B18-2 without furtherpurification.

Step 2. Preparation of N-(3-cyano-4-methyl-phenyl)-methanesulfonamide(B18-2)

A solution of B18-1 (18 g, 136.36 mmol) in pyridine (150 mL) was cooledto 0° C. and treated with mesyl chloride (12.6 mL, 163.63 mmol). Themixture was allowed to warm to 25° C., stirred for 20 hours, andconcentrated. The resultant residue was diluted with EtOAc (500 mL), andwashed with 2N HCl (50 mL), water (100 mL), and brine (50 mL). Theorganic solution was then dried over anhydrous sodium sulfate andconcentrated to provide B18-2 as a yellow solid. Yield: 25.1 g, 87.3%.¹HNMR(CDCl₃): δ 7.5 (s, 1H), 7.3-7.45 (m, 2H), 7.1-7.25 (m, 1H), 3.05(s, 3H) and 2.5 (s, 3H). Mass: (M+1) 209 calculated for C₉H₁₀N₂O₂S.

Step 3. Preparation ofN-(3-cyano-4-methyl-phenyl)-N-methyl-methanesulfonamide (B18-3)

A solution of B18-2 (25 g, 119.04 mmol) in a mixture of THF (200 mL) and40% NaOH solution (200 mL) at 25° C. was treated with BTEAC (2.7 g, 11.9mmol) and stirred vigorously for 20 minutes. The mixture was thentreated with methyl iodide (8.89 mL, 142.8 mmol), stirred for 20 hours,and concentrated. The resultant residue was extracted with DCM (500 mL)and washed with water (100 mL) and brine (50 mL). The organic solutionwas dried over anhydrous sodium sulfate and concentrated. The resultantresidue was purified by column chromatography (60-120 mesh silica gel;40% EtOAc in hexane as eluting solvent) to provide B18-2 as a whitesolid. Yield: 26.2 g, 97%. ¹HNMR(CDCl₃): δ 7.55-7.65 (m, 1H), 7.5-7.54(m, 1H), 7.3-7.4 (m, 1H), 3.34 (s, 3H), 2.85 (s, 3H) and 2.55 (s, 3H).Mass: (M+1) 225 calculated for C₁₀H₁₂N₂O₂S.

Step 4

A solution of B18-3 (28 g, 124.4 mmol) in acetic acid (500 mL) and THF(200 mL) was charged to a Parr reactor and treated with 10% Pd/C (8 g).The contents of the reactor were then hydrogenated at 50 PSi hydrogenpressure and 25° C. for 4 hours. The mixture was filtered through aCelite® bed and washed with ethanol (50 mL). The combined filtrates wereconcentrated, and the resultant residue was azeotroped with EtOAc (3×50mL). The resultant oily residue was dissolved in EtOAc (200 mL) andmaintained at 25° C. for 20 hours. The resultant solids were collectedand dried to provide B18 as a white solid. Yield: 2.9 g, 81%. ¹HNMR(d₆-DMSO): δ 7.42 (s, 1H), 7.15 (s, 2H), 5.7-5.98 (broad, 3H), 3.72 (s,2H), 3.2 (s, 3H), 2.95 (s, 3H), 2.25 (s, 3H) and 1.86 (s, 3H). Mass:(M+1) 229 calculated for C₁₀H₁₆N₂O₂S. HPLC Purity: 99.9%.

Preparation ofN-(5-Aminomethyl-2-methyl-pyrimidin-4-yl)-N-methyl-methansulfonamideacetate (B19)

Step 1. Preparation of4-hydroxy-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester(B19-1)

A mixture of water (410 mL) and a 50% NaOH solution (115.98 g, 2899mmol) was cooled to 0° C. and treated with 2-methyl 2-thio pseudo ureasulfate (100 g, 359 mmol). The resultant clear solution was treated witha solution of ethoxy methylene malonate (155.38 g, 719 mmol) in ethanol(251 mL) and stirred until the reaction mixture was turbid. The mixturewas then allowed to warm to 25° 5, and it was allowed to stand at 25° C.for 20 hours. The resultant solids were collected, washed with ethanol(2×50 mL), and dried under reduced pressure to provide B19-1 as a paleyellow solid. Yield: 58 g, 75%. ¹HNMR (d₆-DMSO): δ 8.25 (s, 1H), 4.12(q, 2H), 2.32 (s, 3H) and 1.24 (t, 3H).

Step 2. Preparation of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylicacid ethyl ester (B19-2)

Neat POCl₃ (120 mL) was cooled to 10° C. and treated portion-wise over 4hours with B19-1 (50 g, 232 mmol) without exceeding a temperature of 25°C. The mixture was then heated at 65° C. After 3 hours the mixture wascooled to 10° C., poured into crushed ice (350 g), treated drop-wisewith water (676 mL) under vigorous stirring. The resultant solids werecollected and dried under reduced pressure to provide B19-2 as a paleyellow solid. Yield: 22 g, 40%. ¹HNMR (CDCl₃): δ 8.95 (s, 1H), 4.44 (q,2H), 2.62 (s, 3H) and 1.42 (t, 3H).

Step 3. Preparation of4-chloro-2-methanesulfonyl-pyrimidine-5-carboxylic acid ethyl ester(B19-3)

A solution of B19-2 (40 g, 172 mmol) in methanol (720 mL) was cooled to0° C. and treated with a slurry of oxone (317.9 g, 517 mmol) indistilled water (720 mL). The mixture was allowed to warm to 25° C. andstirred at 5 hours. The mixture was filtered, and the solids were washedwith DCM (500 mL). The resultant organic layer was collected, and theaqueous layer was extracted with DCM (3×200 mL). The combined organiclayers were then washed with brine, dried over anhydrous sodium sulfate,and concentrated to provide B19-2 as a white solid. Yield: 31 g, 68%. IR(cm⁻¹): 3015, 2932, 1734, 1550, 1445, 1391, 1325, 1258, 1222, 1142 and1067. ¹HNMR (CDCl₃): δ 9.28 (s, 1H), 4.5 (q, 2H), 3.4 (s, 3H) and 1.45(t, 3H). Mass: (M+1) 265 calculated for C₈H₉ClN₂O₄S.

Step 3. Preparation of 4-chloro-2-methyl-pyrimidine-5-carboxylic acidethyl ester (B19-3)

A solution of B19-2 (40 g, 151 mmol) in THF (700 mL) was cooled to 0° C.and treated drop-wise over 2 hours with a 3 molar solution of methylmagnesium chloride in THF (54 mL, 166 mmol). The mixture was allowed towarm to 25° C. and maintained for at 25° C. for 4 hours. The mixture wasadded to water (500 mL) and extracted with EtOAc (3×300 mL). Thecombined organic layers were washed with brine (250 mL), dried overanhydrous sodium sulfate, and concentrated to provide B19-2 as a brownliquid. Yield: 30 g, 98%. IR (cm⁻¹): 2983, 2934, 2868, 1736, 1574, 1523,1434, 1373, 1269, 1181 and 1070. ¹HNMR (CDCl₃): δ 9.1 (s, 1H), 4.5 (q,2H), 2.74 (s, 3H) and 1.5 (t, 3H).

Step 3. Preparation of4-(methanesulfonyl-methyl-amino)-2-methyl-pyrimidine-5-carboxylic acidethyl ester (B19-3)

A solution of N-methyl methane sulphonamide (18.2 g, 180 mmol) inacetonitrile (420 mL) was cooled to 0° C. and treated with cesiumcarbonate (68 g, 225 mmol). The mixture was then treated over 2 hourswith B19-2 (30 g, 150 mmol). The mixture was allowed to warm to 25° C.,and it was maintained at 25° C. for 20 hours. The mixture was thenfiltered, and the solids were washed with washed with EtOAc (200 mL).The combined filtrates were further diluted with EtOAc (500 mL), washedwith water (2×500 mL) and brine, and dried over anhydrous sodiumsulfate. The organic solution was then concentrated to provide B19-3 asan orange solid. Yield: 18 g, 44%. ¹HNMR (d₆-DMSO): δ 8.94 (s, 11-H),4.3 (q, 2H), 3.25-3.3 (m, 6H), 2.65 (s, 3H) and 1.3 (t, 3H). Mass: (M+1)274 calculated for C₁₀H₁₅N₃O₄S.

Step 4. Preparation of4-(methanesulfonyl-methyl-amino)-2-methyl-pyrimidine-5-carboxylic acidamide (B19-4)

A suspension of 819-3 (10 g, 36 mmol) in 25% NH₄OH (100 mL) was heatedat 32° C. for 20 hours. The mixture was concentrated under reducedpressure, and the resultant residue was triturated with EtOAc. Themixture was then filtered and concentrated. The resultant residue waspurified by column chromatography (60-120 mesh silica gel; 10% MeOH inCHCl₃ as eluting solvent) to provide B19-4 as a white solid. Yield: 3 g,33%. ¹HNMR (d₆-DMSO): δ 8.75 (s, 1H), 7.95 (s, 1H), 7.7 (s, 1H),3.3-3.42 (m, 3H), 3.25 (s, 3H) and 2.65 (s, 3H). Mass: (M+1) 245calculated for C₈H₁₂N₄O₃S.

Step 5. Preparation ofN-(5-cyano-2-methyl-pyrimidin-4-yl)-N-methyl-methanesulfonamide (B19-5)

A solution of B19-4 (5.2 g, 22.3 mmol) and pyridine (3.36 g, 42.6 mmol)in 1,4 dioxane (78 mL) was cooled to 0° C. and treated drop-wise over 10minutes with TFA (5.8 g, 27.7 mmol). The mixture was allowed to warm to25° C. After 4 hours the mixture was diluted with EtOAc (100 mL) andwashed with water (2×200 mL). The aqueous layer was collected and washedwith EtOAc (2×100 mL). The combined organic layers were then washed withbrine (100 mL), dried over anhydrous sodium sulfate, and concentrated.The resultant residue was then washed with petroleum ether and dried toprovide B19-5 as a pale yellow solid. Yield: 3.5 g, 76%. ¹HNMR (CDCl₃):δ 8.84 (s, 1H), 3.54 (s, 3H), 3.4 (s, 3H) and 2.75 (s, 3H). Mass: (M−1)225 calculated for C₈H₁₀N₄O₂S.

Step 6

A solution of B19-5 (5 g, 22 mmol) in 2N methanolic ammonia (350 mL) wascharged to a Parr reactor and treated with 10% Pd/C (3.75 g, 35 mmol).The contents of the reactor were then hydrogenated at 48 Psi hydrogenpressure and 25° C. for 1 hour. The mixture was filtered through aCelite® bed and washed with methanol (200 mL). The combined filtrateswere concentrated, and the resultant residue was diluted with EtOAc (25mL) and acetic acid (1.3 g, 21 mmol). The mixture was stirred for 30minutes, and the resultant solids were collected to provide B19 as awhite solid. Yield: 4.2 g, 80%. IR (cm⁻¹): 3433, 3381, 3017, 2930, 1720,1591, 1555, 1446, 1331, 1148 and 1058. ¹HNMR (d₆-DMSO): δ 9.05 (s, 1H),8.5-8.7 (broad s, 2H), 4.14 (s, 2H), 3.24 (s, 3H), 3.15 (s, 3H) and 2.66(s, 3H). HPLC Purity: 99.9%.

4-Chloro-pyrimidine intermediates were prepared by methods similar tothat described below for compound B20.

Preparation of4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-N-methylbenzamide(B20)

A solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (8.63 mmol) in1:1 t-BuOH/DCE (10 mL) was cooled to 5° C., treated with solid ZnBr₂(22.5 mmol), and stirred at 5° C. for 30 minutes. The resultant solutionwas maintained at 5° C. and treated first with solid4-amino-N-methyl-benzamide (7.5 mmol) followed by TEA (16.5 mmol). Theresultant white mixture was allowed to warm 25° C., and it was mixed at25° C. for 20 hours. The mixture was adsorbed onto silica gel, and thefraction eluting 0-10% methanol/DCM was collected and concentrated. Theresultant residue was triturated with water and filtered to provide B20.Yield: 3.0 mmol, 40%. LCMS 2.3 min, MZ+=331.1 ¹H NMR (500 MHz, d₆-DMSO)δ ppm 10.89 (s, 1H), 8.87 (s, 1H), 8.34 (d, J=4.67 Hz, 1H), 7.73-7.89(m, 3H), 2.78 (d, J=4.67 Hz, 3H).

Example 1 (R)-tert-butyl1-(4-(4-((2-(N-methylmethan-5-ylsulfonamido)pyridin-3-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate(1)

Step 1: Preparation of (R)-tert-butyl 1-(4-nitrophenyl)ethylcarbamate(C1)

(R)-1-(4-nitrophenyl)ethanamine hydrochloride salt (1.0 g, 4.9 mmol),tert-butoxycarbonyl (BOC) anhydride (1.18 g, 5.43 mmol), and 10.0 mL of1M sodium bicarbonate solution were dissolved in DCM (15 mL) and allowedto stir at 25° C. for 24 h. The organic layer was collected, and theaqueous layer was washed with DCM. The combined organic layers were thenwashed with water and 0.1N HCl, dried over MgSO₄, filtered, andconcentrated to provide C1 as a white solid. Yield: 1.2 g, 92%.GC-MS=266. ¹H NMR (500 MHz, d₆-DMSO) δ: 8.15 (d, 2H), 7.56 (d, 1H), 7.52(d, 2H), 4.68 (m, 1H), 1.32 (s, 9H), 1.27 (d, 3H).

Step 2: Preparation of (R)-tert-butyl 1-(4-aminophenyl)ethylcarbamate(C2)

A solution of C1 (1.0 g, 3.8 mmol) in MeOH (20 mL) was charged to a Parrreactor, and the contents of the reactor were treated with 10% Pd/C (800mg, 0.376 mmol). The contents of the reactor were then hydrogenated at45 Psi hydrogen pressure and 25° C. for 4 hours. The contents of thereactor were filtered through Celite® and washed with DCM. The combinedfiltrates were concentrated to provide C2 as a sticky orange residue.Yield: 690 mg, 78% yield. GC_MS=236. ¹H NMR (500 MHz, d₆-DMSO) δ: 7.07(d, 1H), 6.88 (d, 2H), 6.43 (d, 2H), 4.85 (s, 2H), 4.40 (m, 1H), 1.31(s, 9H), 1.18 (d, 3H).

Step 3. Preparation of (R)-tert-butyl1-(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate(C3)

C2 (690 mg, 2.92 mmol) was dissolved in 10 mL DCE:t-BuOH (1:1 vol:vol),and the resultant solution was treated with ZnBr₂ (1.97 g, 8.76 mmol)and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (748 mg, 3.45 mmol). Theresultant mixture was then treated drop-wise with TEA (406 ml, 2.92mmol), and the mixture was allowed to stir at 25° C. for about 20 hours.The reaction mixture was concentrated, and the resultant residue wastreated with EtOAc. The resultant solution was washed with water andbrine, and dried over MgSO₄. The mixture was then filtered,concentrated, and purified by column chromatography eluting with 22%EtOAc/Heptane. The product-containing eluents were combined andconcentrated to provide C3 as a white solid. Yield: 680 mg, 56%.MS-415.2. ¹H NMR (500 MHz, DMSO) δ: 10.59 (s, 1H), 8.74 (s, 1H), 7.53(d, 2H), 7.31 (d, 1H), 7.23 (d, 2H), 4.54 (m, 1H), 1.33 (s, 9H), 1.25(d, 3H).

Step 4

Compound C3 (100 mg, 0.24 mmol), B5 (B8.5 mg, 0.264 mmol), anddiethylamine (DIEA) (0.127 ml, 0.960 mmol) were dissolved in1,2-dichloroethane (DCE):t-BuOH (1:1 vol:vol) (1.2 mL). The resultantsolution was heated at 80° C. for about 20 hours, cooled to 25° C.,treated with EtOAc, and washed with water. The organic phase wascollected, and the aqueous phase was washed with EtOAc. The combinedorganic layers were dried over MgSO₄, filtered, and concentrated toprovide 1 as a sticky residue. MS⁺ 596.8. ¹H NMR (500 MHz, d₆-DMSO) δ:9.50 (s, 1H), 8.41 (m, 1H), 8.22 (s, 1H), 7.61 (m, 2H), 7.35 (m, 3H),6.99 (d, 2H), 4.76 (d, 2H), 4.47 (m, 1H), 3.14 (s, 3H), 3.11 (s, 3H),1.33 (s, 9H), 1.21 (d, 3H). The product was used in the preparation ofcompound 2 in Example 2 below without further purification.

Example 2 Preparation of(R)—N-(3-((2-(4-(1-aminoethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamidehydrochloride (2)

A solution of 1 (143 mg, 0.24 mmol) in THF (0.3 mL) was treated with 4NHCl in dioxane (0.240 ml, 0.96 mmol), and stirred at 25° C. for about 20hours. The reaction mixture was then triterated with EtOAc and filtered,and the filtrate was concentrated to provide the HCl salt form of 2 as awhite solid. Yield: 128 mg, 94% yield. MS⁻ 494.0. ¹H NMR (500 MHz,d₆-DMSO): δ 10.2 (s, 1H), 8.40 (m, 4H), 8.12 (s, 1H), 7.67 (d, 1H), 7.45(m, 3H), 7.27 (d, 2H), 4.84 (d, 2H), 4.28 (m, 1H), 3.16 (s, 3H), 3.14(s, 3H), 1.45 (d, 3H). FAK IC₅₀: <0.000595 μM (Table 1, Example 354)

Example 3 Preparation of tert-butyl4-(4-((2-(N-methylmethan-5-ylsulfonamido)pyridin-3-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzylcarbamate(3)

Step 1: Preparation of tert-butyl 4-nitrobenzylcarbamate (C4)

A stirred solution of (4-nitrophenyl)methanamine hydrochloride (10 g,53.0 mmol) in THF (150 mL) and water (13 mL) was cooled to 0° C. andtreated with BOC anhydride (11.6 g, 53.0 mmol) and DIEA (27.7 mL, 159mmol). The reaction mixture was stirred for about 20 hours as it wasallowed to warm to 25° C. The mixture was then concentrated, and theresultant residue was dissolved in EtOAc. The resultant solution waswashed with 1N HCl, saturated sodium bicarbonate, and brine. The organicphase was then dried over MgSO₄, filtered, and concentrated to provideC4 as an off white solid. Yield: 14.0 g, 99%. ¹H NMR (400 MHz, d₆-DMSO)δ: 8.16 (d, 2H), 7.55 (t, 1H), 7.46 (d, 2H), 4.21 (d, 2H), 1.36 (s, 9H).

Step 2. Preparation of tert-butyl 4-aminobenzylcarbamate (C5)

C4 (7.0 g, 27.7 mmol) was dissolved in dioxane (325 mL), ethanol (240mL), and water (160 mL). The resultant solution was then treated withFe(0) powder (7.12 g, 127.4 mmol) and ammonium chloride (5.33 g, 99.7mmol), and the resultant mixture was stirred at 70° C. for 4 hours. Thereaction mixture was cooled to 25° C., filtered through Celite®, andwashed with EtOAc. The organic solvents were evaporated, and theresultant aqueous residue was extracted with EtOAc. The combined organiclayers were dried over MgSO₄, filtered, and concentrated to provide C5as a yellow solid. Yield: 6.52 g, 99% yield. ¹H NMR (400 MHz, d₆-DMSO)δ: 7.146 (t, 1H), 6.87 (d, 2H), 6.48 (d, 2H), 4.95 (s, 2H), 3.92 (d,2H), 1.38 (s, 9H).

Step 3. Tert-butyl4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)benzylcarbamate (C6)

Compound C6 was prepared as a white solid in a manner similar to thatdescribed in Step 3 of Example 1 except that C5 (1.30 g, 5.86 mmol) wasused instead of C2. Yield: 1.37 g, 49%. MS⁻ 401.1. ¹H NMR (400 MHz,d₆-DMSO) δ: 10.6 (s, 1H), 8.75 (s, 1H), 7.56 (d, 2H), 7.34 (t. 1H), 7.18(d, 2H), 4.05 (d, 2H), 1.36 (s, 9H).

Step 4

Compound 3 was prepared as a white solid in a manner similar to thatdescribed in Step 4 of Example 1 except that C6 (1.2 g, 2.98 mmol) wasused instead of C3, and the resultant crude product was purified bycolumn chromatography, eluting with 45-55% EtOAc/Heptane. Yield: 1.17 g,68%. MS⁺ 582.3. ¹H NMR (500 MHz, d₆-DMSO) δ: 9.57 (s, 1H), 8.42 (s, 1H),8.58 (s, 1H), 7.64 (m, 2H), 7.35 (m, 4H), 6.94 (d, 2H), 4.80 (d, 2H),3.98 (d, 2H), 3.16 (s, 3H), 3.14 (s, 3H), 1.39 (s, 9H).

Example 4 Preparation ofN-(3-((2-(4-(aminomethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide(4)

The HCl salt form of 4 was prepared as a white solid in a manner similarto that described for preparing 2 in Example 2 except that 3 (1.0 g,1.72 mmol) was used instead of 1.

The salt form of 4 was dissolved in DCM, and was washed with saturatedsodium bicarbonate. The organic phase was then dried over Na₂SO₄,filtered, and concentrated to provide the free-base form of 4 as a foamywhite solid. Yield: 904 mg, 99%. MS' 482. ¹H NMR (500 MHz, d₆-DMSO) δ:9.50 (s, 1H), 8.44 (d, 1H), 8.25 (s, 1H), 7.66 (d, 1H), 7.57 (t, 1H),7.38 (m, 3H), 7.04 (d, 2H), 4.80 (d, 2H), 3.58 (d, 2H), 3.17 (s, 3H),3.13 (s, 3H). FAK IC₅₀: 0.00059 μM (Table 1, Example 104)

Example 5 Preparation ofN-(4-(4-((2-(N-methylmethan-5-ylsulfonamido)pyridin-3-yl)methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzyl)acetamide(5)

The free-base form of 4 (B0 mg, 0.166 mmol), acetic anhydride (0.019 ml,0.199 mmol), and DIEA (0.043 ml, 0.249 mmol) were dissolved in THF (0.5ml) and stirred at 25° C. for 24 hours. The reaction mixture was thentreated with EtOAc and washed with 1N NaOH. The resultant organic layerwas dried over MgSO₄, filtered, and concentrated to provide 5 as a whitesolid. Yield: 63 mg, 73%. MS⁺ 524.5. ¹H NMR (500 MHz, d₆-DMSO) δ: 9.55(s, 1H), 8.44 (d, 1H), 8.25 (s, 1H), 8.22 (t, 1H), 7.60 (m, 2H), 7.38(m, 3H), 6.96 (d, 2H), 4.80 (d, 2H), 4.11 (d, 2H), 3.16 (s, 3H), 3.13(s, 3H), 1.85 (s, 3H). FAK IC₅₀: 0.0006 μM

Example 6 Preparation ofN-(3-((2-(4-(hydroxymethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide(6)

Step 1. Preparation of(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)methanol (C7)

Step 1

C7 was prepared in a manner similar to that described in for making C3in Step 3 of Example 1 except that 4-aminobenzyl alcohol (2.4 g, 19mmol) was used instead of C2. When the reaction was complete thereaction mixture was concentrated and dissolved in EtOA. The resultantsolution was washed with water, brine, dried over MgSO₄, andconcentrated. The resultant tan solid was triterated with ether and asmall amount of EtOAc, filtered and concentrated to provide C7 as a tansolid. Yield: 2.98 g, 50%. MS⁺ 304.1. ¹H NMR (500 MHz, d₆-DMSO) δ: 10.61(s, 1H), 8.76 (s, 1H), 7.59 (d, 2H), 7.26 (d, 2H), 5.10 (bs, 1H), 4.43(s, 2H).

Step 2

Compound 6 was prepared in a manner similar to that described for makingcompound 1 in Step 4 of Example 1, except that C7 (2.5 g, 8.2 mmol) wasused instead C3. When the reaction was complete the reaction mixture wasconcentrated and dissolved in EtOA. The resultant solution was washedwith water, brine, and dried over MgSO₄, and concentrated. The resultantsolid was triterated with hot EtOAc, and the mixture was cooled to 0° C.and filtered to provide 6 as a white solid. Yield: 2.94 g, 74%. MS⁺483.4. ¹H NMR (500 MHz, d₆-DMSO) δ: 9.50 (s, 1H), 8.41 (d, 1H), 8.22 (s,1H), 7.62 (d, 1H), 7.55 (t, 1H), 7.36 (m, 3H), 6.99 (d, 2H), 4.98 (t,1H), 4.76 (d, 2H), 4.32 (d, 2H), 3.13 (s, 3H), 3.11 (s, 3H). FAK IC₅₀:<0.000595 μM (Table 1, Example 319)

Example 7 Preparation ofN-(3-((2-(4-(chloromethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide(7)

A suspension of 6 (800 mg, 1.66 mmol) in DCM (5 mL) was cooled to 0° C.and treated with a solution of thionyl chloride (0.266 ml, 3.65 mmol) inDCM (2.0 mL). The reaction mixture was allowed to warm to 25° C. andstirred at 25° C. for 20 hours. The reaction mixture was then treatedwith DCM and washed with water (2×). The aqueous layer was collected andwashed with DCM. The combined organic layers were then dried over MgSO₄,filtered and concentrated to provide 7 as a white solid. Yield: 668 mg,80%. ¹H NMR (500 MHz, d₆-DMSO) δ: 6.68 (s, 1H), 8.45 (d, 1H), 8.28 (s,1H), 7.64 (m, 2H), 7.42 (m, 3H), 7.14 (d, 2H), 4.82 (d, 2H), 4.66 (s,2H), 3.17 (s, 3H), 3.15 (s, 3H). FAK IC₅₀: 0.00155 μM (Table 1, Example348)

Example 8 Preparation ofN-(3-((2-(4-((1,3-dihydroxypropan-2-ylamino)methyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide(8)

A mixture of 7 (100 mg, 0.200 mmol), 2-amino-1,3-propanediol (90.9 mg,0.998 mmol), sodium hydroxide (7.98 mg, 0.200 mmol) and 2-propanol (0.5mL) was heated to reflux. After 30 minutes the mixture was cooled,treated with DCM, and washed with water. The organic phase was driedover MgSO₄, filtered and concentrated. The resultant residue was thenpurified by column chromatography (silica gel; eluting with 6% MeOH/DCMwith NH₄OH), and the eluents containing the product were combined andconcentrated to provide 8 as a white solid. Yield: 60.9 mg, 55%. MS'556.2. ¹H NMR (500 MHz, d₆-DMSO) δ: 9.48 (s, 1H), 8.41 (s, 1H), 8.21 (s,1H), 7.59 (m, 2H), 7.34 (m, 3H), 6.99 (d, 2H), 4.75 (d, 2H), 4.35 (t,2H), 3.58 (s, 2H), 3.34 (m, 4H), 3.12 (s, 3H), 3.09 (s, 3H), 2.45 (m,1H). FAK IC₅₀: <0.000595 μM (Table 1, Example 389)

Example 9 Preparation of tert-butyl3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzoate(9)

Step 1. Preparation of tert-butyl3-({4-chloro-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzoate (C8)

A solution of pyrimidine (24.8 g, 115 mmol) in tert-butanol (150 mL) andDCE (150 mL) was treated with ZnBr₂ (25.8 g, 115 mmol), and theresultant mixture was stirred at 25° C. until all the ZnBr₂ dissolved.The resultant solution was cooled to 0° C. and treated drop-wise withaniline (22.13 g, 115 mmol). The resultant brown mixture was thentreated drop-wise with DIEA (40.1 mL, 230 mmol). The mixture was allowedto warm to 25° C. and stirred for 16 hours under N₂ atmosphere. Themixture was concentrated, and the resultant residue was suspended inMeOH. The resultant white solids were collected to provide C8 as a whitesolid. Yield: 22.7 grams, 53%. APCI m/z 371.8/373.8 (M⁻); ¹H NMR(d₆-DMSO) δ: 10.84 (bs, 1H), 8.85 (s, 1 h), 8.37 (bs, 1H), 7.92 (d,J=7.8 Hz., 1 h), 7.62 (d, J=7.8 Hz., 1H), 7.48 (t, J=7.8 Hz., 1H), 1.56(s, 9H) ppm.

Step 2

A solution of tert-butanol (20.0 mL), DCE (20.0 mL) and DIEA (3.13 mL,18.0 mmol) was treated with C8 (5.60 g, 15.0 mmol) and B5 (5.02 g, 15.0mmol), and the resulting mixture was stirred at 80° C. under anatmosphere of nitrogen for 16 hours. The mixture was cooled to 25° C.and concentrated. The resultant residue was partitioned between EtOAcand 1 N sodium hydroxide, and the organic phase was collected. Theaqueous layer was extracted with EtOAc, and the combined organic phaseswere dried over MgSO₄ and filtered. The resultant filtrate wasconcentrated under reduced pressure, and the resultant residue wastriturated with hot EtOAc to provide 9 as a white solid. Yield: 7.83grams, 95%. LC/MS (standard) 25°=3.0 min., m/z 553.6 (MH⁺). HPLC (FAK1)25°=8.14 min. ¹H NMR (d₆-DMSO) δ: 9.75 (bs, 1H), 8.44 (d, J=5.2 Hz.,1H), 8.29 (s, 1H), 8.05 (bs, 1H), 7.82 (d, J=7.8 Hz., 1H), 7.60 (t,J=5.7 Hz., 1H), 7.44-7.40 (m, 2H), 7.17 (t, J=5.7 Hz, 1H), 4.82 (d,J=5.7 Hz., 2H), 3.16 (s, 3H), 3.13 (s, 3H), 1.51 (s, 9H) ppm. FAK IC₅₀:0.0006 μM

Example 10 Preparation of3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzoicacid trifluoroacetic acid salt (10)

A solution of 9 (7.83 g, 14.1 mmol) in DCE (30.0 mL) was cooled to 00°C. and treated slowly with TFA (45.0 mL). The resultant orange-brownsolution was allowed to slowly warm to 25° C. under an N₂ atmosphere andstirred for 4 hours. The mixture was then concentrated, and theresultant residue was treated with EtOAc. The resultant white solidswere collected by filtration and washed with EtOAc to provide thetrifluoroacetate salt form of 10. Yield: 7.24 grams, 84%. APCI m/z 496.8(MH⁺), HPLC (FAK1) 25°=5.29 min., 1H NMR (d₆-DMSO) δ: 9.82 (bs, 1H),8.44 (d, J=5.2 Hz., 1H), 8.29 (s, 1H), 8.08 (bs, 1H), 7.79 (d, J=7.8Hz., 1H), 7.60-7.38 (m, 4H), 7.17 (t, J=5.7 Hz, 1H), 4.82 (d, J=5.7 Hz.,2H), 3.16 (s, 3H), 3.13 (s, 3H) ppm. FAK IC₅₀: 0.0006 μM

Example 11 Preparation ofN-cyclopropyl-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamide(11)

A polymer supported carbodiimide (PS-CDI) (0.326 mmol) was allowed toswell in acetonitrile (volume of 500 μL). The resultant suspension wastreated with 10 (100 mg, 0.164 mmol) and DIEA (29 μL, 0.164 mmol). Theresultant solution was then treated with cyclopropylamine (19 μL, 0.164mmol). The resultant suspension was then mixed on a shaker plate for 16hours. The mixture was then filtered, and the solids washed with 10%MeOH in chloroform. The combined filtrates were concentrated underreduced pressure, and the resultant residue was purified over silica(99:1:0.1 CHCl₃:CH₃OH:NH₄OH) to provide 11 as a white foam. Yield: 14.3mg, 16%. LC Ret. Time (standard)=2.1 min., m/z 536.2 (MH⁺); ¹H NMR(CD₃OD) δ: 8.42 (d, J=7.8 Hz., 1H), 8.20 (s, 1 h), 7.97 (t, J=7.8 Hz.,1H), 7.81 (d, J=7.8 Hz., 1H), 1.68 (d, J=7.8 Hz., 1H), 7.39-7.34 (m,2H), 7.26 (t, J=7.8 Hz., 1H), 4.94 (s, 2H), 3.23 (s, 3H), 3.14 (s, 3H),2.82 (m, 1H), 0.79 (m, 2 h), 0.60 (m, 2H) ppm. FAK IC₅₀: 0.00186 μM

Example 12 Preparation ofN-(3-((2-(4-(1-hydroxyethyl)phenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamnide(12)

Step 1.N-(3-((2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)methyl)pyridin-2-yl)-N-methylmethanesulfonamide(C9)

A solution of B5 and trifluoroethanol (120 mL) was treated withtriethylamine (TEA) (16.6 mL) and stirred at 25° C. for 1 hour. In aseparate reaction flask, a solution of2,4-dichloro-5-trifluoromethylpyrimidine (13.2 g, 60.8 mmol) andtrifluoroethanol (120 mL) was cooled to −45° C. The cold2,4-dichloro-5-trifluoromethylpyrimidine solution was then treateddrop-wise with the solution containing B5 and stirred at −45° C. for 2hours. The mixture was allowed to warm to 25° C., and it was stirred at25° C. for about 20 hours. The reaction mixture was then concentratedand cooled to 0° C. The resultant white mixture was diluted with EtOAc(15 ml), and the solids collected by filtration. The white solids werethen washed with water and EtOAc to provide C9. Yield: 0.7 g, 45%. ¹HNMR (400 MHz, d₆-DMSO) δ: 3.07 (s, 3H), 3.29 (s, 3H), 4.68 (d, 2H), 7.39(m, 1H), 7.72 (d, 1H), 8.40 (s, 1H), 8.50 (t, 1H); ESI-MS: 396.0 (MH⁺).

Step 2

A solution of C9 (0.253 mmol) and anhydrous DMSO (0.5 ml) was treatedwith 1-(4-aminophenyl)ethanol (0.277 mmol) followed by potassiumphosphate dibasic (0.746 mmol). The mixture was stirred at 100° C. for1.5 days, and treated with additional 1-(4-aminophenyl)ethanol (0.583mmol). The mixture was stirred at 100° C. for 15 hours and concentrated.The resultant residue was purified first by column chromatography(silica gel; 10% (NH₄OH/MeOH)/CH₂Cl₂) followed by preparatory thin layerchromatography developed in 5% MeOH/CH₂Cl₂ to provide 12. Yield: 13.6mg, 10.8%. ¹H NMR (CD₃OD) δ: 8.39 (d, 1H), 8.13 (s, 1H), 7.73 (d, 1H),7.33 (m, 3H), 7.14 (d, 2H), 4.87 (s, 2H), 4.72 (q, 1H), 3.17 (s, 3H),3.10 (s, 3H), 1.37 (d, 3H). MS: m/z 497 (MH⁺).

Example 13 Preparation of2-fluoro-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamideformic acid salt (13)

A mixture of 4-amino-2-fluorobenzamide (1.5 eq., 189 μM) in 2-propanol(1.0 mL) was treated with C9 (1 equiv., 130 uM) followed bytrifluoroacetic acid (2.7 equiv., 341 μM) and stirred in a sealed vialat 100° C. for about 20 hours. The mixture was then cooled to 25° C.,treated with DMSO, filtered, and purified on a Shimadzu using a reversephase Symmetry C-8 column and eluting with 20-80% B for 10 min at 40ml/min (A: 0.1% formic acid in water, B: 0.1% formic acid inacetonitrile to provide the formic acid salt of 13 as a cream coloredsolid. Yield: 17.5 mg, 27%. LC-MS M+1=514. NMR (d₆-DMSO) $: 3.13 (6H,s), 4.81 (2H, s), 7.30-7.40 (6H, m), 7.41-7.73 (2H, m), 8.3 (1H, s),8.41 (1H, s), 9.96 (1H, s). FAK IC₅₀: <0.000595 μM (Table 1, Example320)

Example 14 Preparation of3-fluoro-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzamideformic acid salt (14)

Compound 14 was prepared in a manner similar to that described Example13 for the preparation of 13 except that 4-amino-3-fluorobenzamide (1.5equ/189 μM) was used instead of 4-amino-2-fluorobenzamide to provide theformic acid salt of 14 as a cream colored solid. Yield: 26 mg, 37%.LC-MS M+1=514. NMR (d₆-DMSO) δ: 2.98 (3H, s), 3.09 (3H, s), 4.65 (2H,s), 7.35-7.66 (7H, m), 7.87 (1H, s), 8.23 (1H, s), 8.38 (1H, s), 9.19(1H, s). FAK IC₅₀: <0.000595 μM (Table 1, Example 322)

Example 15 Preparation of4-(4-{[(3-methanesulfonyl-methyl-amino)-pyrazin-2-ylmethyl]-amino}-5-(trifluoromethyl)-pyrimidin-2-ylamino)-N-methyl-benzamide(15)

Step 1

A suspension of B20 (0.3 mmol), B2 (0.3 mmol), and diisopropylethylamine (0.9 mmol) in 1:1 (v:v) DCE/tBuOH was mixed at 80° C. for 9 hours.The mixture was allowed to cool to 25° C., and it was mixed at 25° C.for 20 hours. The mixture was then treated with 9:1 (v:v) ether/ethanol.The solids were collected and washed with water to provide 15. Yield:0.23 mmol, 78%. HPLC (KDC 10_90) 3.526 min. ¹H NMR (500 MHz, d₆-DMSO) δppm 9.83 (s, 1H), 8.69 (d, J=2.59 Hz, 1H), 8.58 (d, J=2.59 Hz, 1H), 8.31(s, 1H), 8.20 (d, J=4.67 Hz, 1H), 7.58-7.70 (m, 3H), 7.41 (t, J=5.18 Hz,1 H), 5.00 (d, J=5.18 Hz, 2H), 3.23 (s, 3H), 3.20 (s, 3H), 2.75 (d,J=4.15 Hz, 3H). FAK IC₅₀: <0.000595 μM (Table 1, Example 317)

Example 15A Preparation of4-(4-{[(3-methanesulfonyl-methyl-amino)-pyrazin-2-ylmethyl]-amino}-5-(trifluoromethyl)-pyrimidin-2-ylamino)-N-methyl-benzamidehydrochloride salt (15A)

Step 1

A suspension of B20 (26.3 mmol), B2 (28.9 mmol) and diisopropylethylamine (105 mmol) was mixed in 1:1 DCE:tBuOH (80 mL) and heated to 88° C.in a sealed flask for 1.5 hour. The mixture turned green and a solidprecipitated. The suspension was diluted with Et2O/EtOH (10:1) andfiltered to obtain 10.1 g of a white solid (75%). 8 g of this productwas slurried in 400 mL of MeOH and to the mixture was added 18 mL 4.0MHCl in dioxane. This was stirred at room temperature for 1 hour, then itwas filtered to obtain 15A as an off-white solid HCl salt (˜quantyield). 1H NMR (400 MHz, DMSO-d₆) δ ppm 2.75 (d, J=3.74 Hz, 3H), 3.18(m, 6H), 5.01 (d, J=4.98 Hz, 2H), 7.52 (d, 2H), 7.67 (d, J=8.72 Hz, 2H),7.98 (br. s., 1H), 8.29 (d, J=4.15 Hz, 1H), 8.42 (s, 1H), 8.59 (d, 1H),8.68 (d, 1H), 10.38 (s, 1H). ESI-MS: 511.1 (MH⁺), 509.2 (M-H)⁻. FAKIC₅₀: 0.00179 μM (Table 1, Example 318)

Examples 16-415

Compounds 16-415 in Examples 16-415 (see Table 1) were prepared by themethods described above in the Detailed Description of the Invention andas described in Examples 1-15A. The amines used in these reactions wereobtained commercially and used as received, prepared as described abovefor compounds B1-B20 or in Examples 1-15A above, or prepared by commonsynthetic methods for amines known to those skilled in the art. Unlessotherwise noted, compounds having chiral centers were prepared asracemic mixtures.

Table 1 also contains biological kinase inhibition (IC50 values) forcompounds 16-415.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying FIGURES. Such modifications are intended to fall within thescope of the appended claims.

TABLE 1 IC50 values against FAK kinase. Ex. Structure Compound Name FAKIC50, μM 16

4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzenesulfon-amide (16) 0.0040917

4-({4-[({6-methyl-2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)benzene-sulfonamide (17) 0.00126 18

4-{[4-{[3-(methylsulfonyl)benzyl]amino}- 5-(trifluoromethyl)pyrimidin-2-yl]amino}benzene-sulfonamide (18) 0.0132 19

4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (19) 0.0034 20

4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (20), hydrochloridesalt 0.0006 21

4-({4-[{{6-methyl-2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(21) 0.001 22

4-{[4-{[3-(methylsulfonyl)benzyl]amino}- 5-(trifluoromethyl)pyrimidin-2-yl]amino}benzamide (22) 0.00356 23

N-methyl-N-[3-({[2-{[6- (methylsulfonyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (23) 0.0686 24

N-4-[3-(methylsulfonyl)benzyl]-N-2-[6- (rnethylsulfonyl)pyridin-3-yl]-5-(trifluoromethyl)-pyrimidine-2,4-diamine (24) 0.337 25

N-methyl-N-[6-methyl-3-({[2-{[6- (methylsulfonyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (25) 0.0129 26

N-methyl-N-[3-({[2-{[6- (methylsulfonyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]methanesulfonamide (26) 0.154 27

N-[3-({[2-{[4-(1,1-dioxidoisothiazolidin- 2-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (27) 0.00138 28

N-[3-({[2-{[4-(1,1-dloxidolsothiazolidin- 2-yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)-6-methylpyridin-2-yl]-N-methylmethanesulfonamide (28) 0.00201 29

N~2~-[4-(1,1-dioxidoisothiazolidin-2- yl)phenyl]-N-4~-[3-(methylsulfonyl)benzyl]-5- (trifluoromethyl)pyrimidine-2,4-diamine (29)0.00209 30

N-methyl-N-{3-[({2-[(4- {[(methylsulfonyl)amino]methyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}methanesulfonamide (30) 0.00072 31

N-[3-({[2-({3- [(aminosulfonyl)methyl]phenyl}amino)-5-(trifluoronnethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonatnide (31) 0.00222 32

N-methyl-N-{3-[({2-[(3- {[(methylsuifonyl)amino]methyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}metlianesulfonamide (32) 33

N-methyl-N-{3-[({2-[(3- {[(methylsulfonyl)amino]methyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl)pyridin-2-yl}methanesulfonamide (33), hydrochloride salt 0.00133 34

4-{[5-bromo-4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)pyrimidin-2- yl)amino}benzenesulfonamide (34) 0.0156 35

4-[(5-bromo-4-{[3- (methylsulfonyl)benzyl]amino}pyrimidin-2-yl)amino]benzene-sulfonamide (35) 0.0176 36

N-methyl-N-[3-({[2-{[1- (methylsulfonyl)piperidin-4-yl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (36) 0.188 37

N-methyl-N-[3-({[2-{[1- (methylsulfonyl)piperidin-4-yl]amino}-5-(trifluoromethyl)pyrimidin-4- yl)amino}methyl)pyridin-2-yl]methanesulfonamide (37), trifluoroacetic acid salt 38

N-[3-({[2-(cyclobutylamino)-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyrldin-2-yl]-N- methylmethane-sulfonamide (38) 0.497 39

N-[3-({[2-{[(3R)-1-acetylpyrrolidin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N- methylmethane-sulfonamide (39) 1 40

methyl 4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzoate(40) 0.00059 41

4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzoic acid (41) 42

4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzoic acid (42), sodium salt0.188 43

4-({4-[({2- [methyl(methylsulfonyl)amino)pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzoic acid (43),trifluoroacetic acid salt 0.0006 44

N-methyl-N-[3-({[2-(piperidin-4-ylamino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (44) 0.188 45

N-{3-[({2-[(1-acetylpiperidin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl)pyridin-2-yl}-N-methylmethane-sulfonamide (45) 0.188 46

N-4-(3-(methylsulfonyl)benzyl]-N-2-phenyl-5-(trifluoromethyl)pyrimidine-2,4- diamine (46) 0.00102 47

3-methoxy-4-{[4-{[3- (methylsulfonyl)benzyl]amino}-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (47) 0.00059 48

3-methoxy-4-({4-[({2- [methyl(methylsuffonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(48) 0.00059 49

3-methoxy-4-({4-[({6-methyl-2- [methyl(methylsulfonyl)-amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrirnidin-2- yl}amino)benzamide(49) 0.00059 50

N-[3-({[2-anilino-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N- methylmethane-sulfonamide (50) 0.0005951

N-[3-({[2-anilino-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)-6-methylpyridin-2-yl]- N-methylmethanesulfonamide (51)0.00059 52

N-methyl-4-{[4-{[3- (methylsulfonyl)benzyl]amino}-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (52) 0.00195 53

N-methyl-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(53) 0.00059 54

N-methyl-4-({4-[({6-methyl-2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(54) 0.00059 55

N-[3-({[2-{[1-(methoxyacetyl)piperidin-4-yl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N- methylmethane-sulfonamide (55) 0.188 56

N-{2-[4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)piperidin-1-yl]-2- oxoethyl}acetamide (56) 0.188 57

4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)piperidine-1-carboxamide (57)0.188 58

N-methyl-N-[3-({[5-(trifluoromethyl)-2-{[1-(3,3,3-trifluoropropanoyl)piperidin-4- yl]amino}pyrimidin-4-yl]amino}methyl)pyridin-2- yl]methanesulfonamide (58) 0.165 59

6-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl )amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)nicotinamide (59) 0.00893 60

ethyl cis-4-({4-(({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)cyclohexanecarboxylate (60) 0.188 61

4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)- N-pyridin-2-ylbenzenesulfonamide(61) 0.00102 62

N-[2-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)-5-methylphenyl]methanesulfonamide (62) 0.0103 63

N-[3-({[2-anilino-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)-4-methylphenyl]-N- methylmethanesulfonamide (63) 0.000664

N-[2-({[2-anilino-5- (trifluoromethyl)pyrimidin-4-yl)amino}methyl)-6-methylphenyl]-N- methylmethanesulfonamide (64) 0.000665

N-[2-({[2-anilino-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)-5-methylphenyl]-N- methylmethanesulfonamide (65) 0.000666

N-[2-({[2-anilino-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)-4-methylphenyl]-N- methylmethanesulfonamide (66) 0.000667

N-[2-({[2-anilino-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)-3-methylphenyl]-N- methylmethanesulfonamide (67) 0.000668

N-[2-(([2-anilino-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)phenyl] methanesulfonamide (68) 0.00059 69

N-[2-({[2-anilino-5- (trifluoromethyl)pyrimidin-4- yl]amino}methyl)-3-methylphenyl]methane-sulfonamide (69) 0.0006 70

N-[3-({[2-anilino-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)-5-methylpyridin-2- yl]-N-methylmethanesulfonamide (70)0.0006 71

4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (71) 0.0006 72

4-({4-[({3- [methyl(methylsulfonyl)amino] pyrazin-2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (72), hydrochloridesalt 73

4-({4-(({3- [methyl(methylsulfonyl)amino]pyridin- 2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (73) 0.0006 74

4-({4-[({3- [methyl(methylsulfonyl)amino]pyridin- 2-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (74), hydrochloridesalt 75

N-[3-({[2-anilino-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyrazin-2-yl]-N- methylmethane-sulfonamide (75) 0.000676

N-[2-({[2-anilino-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-3-yl]-N- methylmethane-sulfonamide (76) 0.093 77

N-ethyl-4-{[4-{[3- (methylsulfonyl)benzyl]amino}-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (77) 0.0006 78

N-[3-({[2-anilino-5- (trifluoromethyl)pyrimidin-4-yl)amino}methyl)-4-methylpyridin- 2-yl]-N-methylmethanesulfonamide (78)0.0006 79

N-[5-({[2-anilino-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)-2-methylpyrimidln- 4-yl]-N-methylmethanesulfonamide(79) 0.00262 80

N-[5-({[2-anilino-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)-2-methylpyridin- 4-yl]-N-methylmethanesulfonamide (80)0.00059 81

N-methyl-N-[3-({[5-(trifluoromethyl)- 2-{[6-(trifluoromethyl)pyridin-3-yl]amino}pyrimidin-4- yl]amino}methyl)pyridin-2- yl]methanesulfonamide(81) 0.0158 82

4-({4-(({5-methyl-2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(82) 0.0006 83

4-({4-[({4-methyl-2- [methyl(methylsulfonyl)amino]pyrldin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(83) 0.0006 84

4-({4-[({2-methyl-4- [methyl(methylsulfonyl)amino] pyrimidin-5-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide (84) 0.0017185

4-({4-[({6-methyl-4- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(85) 0.00084 86

N-methyl-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(86) 0.00161 87

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N-[3-(trifluoromethyl)phenyl]benzamide (87) 88

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N-[3-(trifluoromethyl)phenyl]benzamide (88), hydrochloride salt 0.021589

N-ethyl-4-({4-[({6-methyl-2- [methyl(rnethylsu!fonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(89) 0.0006 90

N-[3-({[2-({3-{(3-hydroxyazetidin-1- yl)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (90) 0.00072 91

N-{3-[({2-[(1-ethyl-1H-pyrazol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (91) 0.188 92

N-{3-[({2-[(2-chloropyridin-4-yl)amino]- 5-(trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (92) 0.0019293

N-{3-[({2-[(2-methoxypyridin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (93) 0.0006 94

N-methyl-N-{3-[({2-[(3-methylpyridin-4-yl)amino]-5-(trifluoromethyl)pyrimidin- 4-yl)amino)methyl]pyridin-2-yl]methanesulfonamide (94) 0.00801 95

N-{3-[({2-[(4-cyanophenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (95) 0.000696

N-methyl-4-{[4-({2- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (96) 0.0005997

N-ethyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(97) 0.00059 98

ethyl [4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)phenyl]acetate (98) 0.00059 99

4-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (99) 0.00038100

4-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (100),hydrochloride salt 101

N-methyl-4-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (101) 0.00059102

N-[5-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)pyridin-2-yl]acetamide (102) 0.00233 103

N-methyl-4-({4-[({6-methyl-4- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(103) 0.00059 104

N-[3-({[2-{[4-(aminomethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (104) 0.00059 105

[4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}arnino)phenyl]acetic acid (105) 0.00094106

4-{[4-({2-methyl-5- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (106) 0.00096107

4-{[4-({2-methyl-6- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifIuoromethyl)pyrimidin-2- yl]amino}benzamide (107) 0.00059108

4-{[4-({3-methyl-2- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (108) 0.0006109

4-{[4-({4-methyl-2- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (109) 0.0006110

4-{[4-({5-methyl-2- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (110) 0.0006111

4-{[4-({2- [(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (111) 0.0006 112

4-{[4-({4-methyl-2- ((methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (112) 0.0006 113

4-{[4-({2-methyl-6- [(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (113) 0.0006 114

N-(2-hydroxyethyl)-N-methyl-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (114) 115

N-(2-hydroxyethyl}-N-methyl-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl)methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (115), trifluoroaceticacid salt 0.00088 116

3-({4-[({2- [methyl(methylsulfonyl)arnino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N- [(2R)-tetrahydrofuran-2-ylmethyl]benzamide (116) 117

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N- [(2R)-tetrahydrofuran-2-ylmethyl]benzamide (117), trifluoroacetic acid salt 0.00147 118

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N-(tetrahydro-2H-pyran-3-yl)benzamide (118) 119

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amlno]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N-(tetrahydro-2H-pyran-3-yl)benzamide (119), trifluoroacetic acid salt0.00114 120

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N-(tetrahydro-2H-pyran-4-yl)benzamide (120) 121

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N-(tetrahydro-2H-pyran-4-yl)benzamide (121), trifluoroacetic acid salt0.00094 122

N-methyl-N-[3-({[2-{[3-(morpholin-4- ylcarbonyl)phenyl)amino}-5-(trifluoromethyl)pyrimidin-4- yl)amino}methyl)pyridin-2-yl]methanesulfonamide (122) 123

N-methyl-N-[3-({(2-{[3-(morpholin-4- ylcarbonyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (123), trifluoroacetic acid salt 0.00215 124

N-[3-({[2-{[3-(azetidin-1 - ylcarbonyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl)-N-methylmethane-sulfonamide (124) 125

N-[3-({[2-{[3-(azetidin-1- ylcarbonyl)phenyl]amino}-5-(trifluoromethyl)pyrimldin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethanesulfon-amide (125), trifluoroacetic acid salt 0.00127 126

N-[(1-hydroxycyclobutyl )methyl]-3-({4-[({2-[methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (126) 127

N-[(1-hydroxycyclobutyl)methyl]-3-({4-[({2-[methyl(methylsulfonyl)amino] pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (127), trifluoroaceticacid salt 0.00211 128

N,N-bis(2-hydroxyethyl)-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (128) 129

N,N-bis(2-hydroxyethyl)-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (129), trifluoroaceticacid salt 0.00076 130

N-cyclopentyl-N-methyl-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (130) 131

N-cyclopentyl-N-methyl-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (131), trifluoroaceticacid salt 0.0108 132

N-[2-(dimethylamino)-2-oxoethyl]-3-({1-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino)-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (132) 133

N-[2-(dimethylamino)-2-oxoethyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (133), trifluoroaceticacid salt 0.00195 134

N-[3-{[2-({3-[(3-hydroxy-3- methylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl)-N- methylmethane-sulfonamide (134) 135

N-[3-({(2-({3-[(3-hydroxy-3- methyipyrrolidin-1-yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N- methylmethane-sulfonamide (135),trifluoroacetic acid salt 0.00333 136

N-[2-(dimethylamino)ethyl]-N-rnethyl-3- ({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (136) 137

N-[2-(dimethylamino)ethyl]-N-methyl-3- ({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino)-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (137), trifluoroaceticacid salt 0.00433 138

3-({4-[({2- [methyl(methylsulfanyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N- (pyridin-2-ylmethyl)benzamide(138) 139

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N- (pyridin-2-ylmethyl)benzamide(139), trifluoroacetic acid salt 0.00191 140

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N-[(3-methyloxetan-3-yl)methyl]benzamide (140) 141

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N-[(3-methyloxetan-3-yl)methyl]benzamide (141), trifluoroacetic acid salt0.00084 142

N-methyl-N-{3-[({2-[(3-{[(3S)-3- methylmorpholln-4-yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2- yl}methanesulfonamide (142) 143

N-methyl-N-{3-[({2-[(3-{[(3S)-3- methylmorpholin-4-yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2- yl}methanesulfonamide (143), trifluoroaceticacid salt 0.0024 144

N-[3-(dimethylamino)propyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (144) 145

N-[3-(dimethylamino)propyl]-3-({4-(({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (145), trifluoroaceticacid salt 0.00254 146

N-{3-[({2-[(3-{[2- (hydroxymethyl)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (146) 147

N-{3-[({2-[(3-{[2- (hydroxymethyl)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (147),trifluoroacetic acid salt 0.00474 148

N-(3-methoxypropyl)-3-({4-[({2- [methyl(methylsulfonyl)-amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(148) 149

N-(3-methoxypropyl)-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(149), trifluoroacetic acid salt 0.00151 150

N-(1-cyclopropylethyl)-3-({4-[({2-[methyl(methylsulfonyl)-amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (150) 151

N-(1-cyclopropylethyl)-3-({4-[({2-[methyl(methylsulfonyl)-amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (151). trifluoroaceticacid salt 0.00524 152

N-{3-[({2-[(3-{((3R,4R)-3,4- difluoropyrrolidin-1-yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (152) 153

N-{3-[({2-[(3-{[(3R,4R)-3,4- difluoropyrrolidin-1-yl]carbonyl}phenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (153),trifluoroacetic acid salt 0.00335 154

N-methyl-N-[3-({[2-({3-[(2- methylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2- yl]methanesulfonamide (154) 155

N-methyl-N-[3-({[2-({3-[(2- methylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2- yl]methanesulfonamide (155), trifluoroaceticacid salt 0.00975 156

N-{3-[({2-[(3-{((3S)-3-hydroxypyrrolidln- 1-yl]carbonyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (156) 157

N-{3-[({2-[(3-{[(3S)-3-hydroxypyrrolidin-1- yl]carbonyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (157), trifluoroacetio acid salt 0.00424 158

N-{3-[({2-[(3-{[(3S)-3-hydroxypiperidin-1- yl]carbonyl}phenyl)amino]-5-(tritluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (158) 159

N-{3-[({2-[(3-{[(3S)-3-hydroxypiperidin-1- yl]carbonyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (159), trifluoroacetic acid salt 0.00614 160

N-[(1R)-1-(hydroxymethyl)-2- methylpropyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (160) 161

N-[(1R)-1-(hydroxymethyl)-2- methylpropyl]-3-({4-(({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (161), trifluoroaceticacid salt 0.00374 162

N-cyclopentyl-3-({4-[({2- (methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(162) 163

N-cyclopentyl-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(163), trifluoroacetic acid salt 0.0051 164

N-{3-[({2-[(3-{[3-(dimethylamino)azetidin-1-yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (164) 165

N-{3-[({2-[(3-{[3-(dimethylamino)azetidin-1-yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- rnethylmethane-sulfonamide (165),trifluoroacetic acid salt 0.00493 166

N-[2-(acetylamino)ethyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (166) 167

N-[2-(acetylamino)ethyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (167). trifluoroaceticacid salt 0.00344 168

N-[(1R)-1-(hydroxymethyl)propyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino)-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (168) 169

N-[(1R)-1-(hydroxymethyl)propyl]-3-({4-(({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (169), trifluoroaceticacid salt 0.00247 170

N-methyl-N-[3-({[2-{[3-(piperidin-1- ylcarbonyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (170) 171

N-methyl-N-[3-({[2-{[3-(piperidin-1- ylcarbonyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (171), trifluoroacetic acid salt 0.00791 172

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N-(1-methylpiperidin-4-yl)benzamide (172) 173

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N-(1-methylpiperidin-4-yl)benzamide (173), trifluoroacetic acid salt0.00096 174

N-{3-[({2-[(3-{[(3R)-3-hydroxypyrrolidin-1- yl]carbonyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (174) 175

N-{3-[({2-[(3-{[(3R)-3-hydroxypyrrolidin-1- yl]carbonyl}phenyl)amino]-5-(trifluoromethyl) pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methyl-methanesulfonamide (175), trifluoroacetic acid salt 0.00408 176

N-[3-({[2-({3-[(3,3-difluoropyrrolidin-1- yl)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl)-N-methylmethane-sulfonamide (176) 177

N-[3-({(2-({3-[(3,3-difluoropyrrolidin-1- yl)carbonyl]phenyl}amino)-5-(trifluoromethyl) pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N-methylmethane- sulfonamide (177), trifluoroaceticacid salt 0.00593 178

N-[(1S)-1-(hydroxymethyl)-2- methylpropyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (178) 179

N-[(1S)-1-(hydroxymethyl)-2- methylpropyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (179), trifluoroaceticacid salt 0.00109 180

N-(3-methoxypropyl)-N-methyl-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (180) 181

N-(3-methoxypropyl)-N-methyl-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (181), trifluoroaceticacid salt 0.00918 182

N-[(1S)-1-(hydroxymethyl)propyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (182) 183

N-[(1S)-1-(hydroxymethyl)propyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (183), trifluoroaceticacid salt 0.00196 184

N-cyclobutyl-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}arnino)benzamide(184) 185

N-cyclobutyl-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(185), trifluoroacetic acid salt 0.00217 186

N-cyclohexyl-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(186) 187

N-cyclohexyl-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(187), trifluoroacetic acid salt 0.00584 188

N-isopropyl-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(188) 189

N-isopropyl-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(189), trifluoroacetic acid salt 0.0043 190

N-benzyl-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(190) 191

N-benzyl-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(191), trifluoroacetic acid salt 0.0055 192

N-(2-hydroxyethyl)-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)-N-propylbenzamide (192) 193

N-(2-hydroxyethyl)-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)-N-propylbenzamide (193), trifluoroacetic acid salt 0.0011 194

N-ethyl-N-(2-methoxyethyl)-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (194) 195

N-ethyl-N-(2-methoxyethyl)-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (195), trifluoroaceticacid salt 0.00681 196

N-methyl-N-[3-({[2-({3-[(4-methylpiperidin-1-yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2- yl]methanesulfonamide (196) 197

N-methyl-N-[3-({[2-({3-[(4-methylpiperidin-1-yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2- yl]methanesulfonamide (197), trifluoroaceticacid salt 0.00447 198

N-methyl-N-[3-({[2-({3-[(4- methylpiperazin-1-yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2- yl]methanesulfonamide (198) 199

N-methyl-N-[3-({[2-({3-[(4- methylpiperazin-1-yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2- yl]methanesulfonamide (199), trifluoroaceticacid salt 0.00256 200

N-(2-hydroxy-1,1-dimethylethyl)-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (200) 201

N-(2-hydroxy-1,1-dimethylethyl)-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (201), trifluoroaceticacid salt 0.00164 202

N-[1-(hydroxymethyl)propyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (202) 203

N-[1-(hydroxymethyl)propyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrirnidin-2- yl}amino)benzamide (203), trifluoroaceticacid salt 0.00113 204

N-[2-(dimethylamino)ethyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (204) 205

N-[2-(dimethylamino)ethyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (205), trifluoroaceticacid salt 0.0032 206

N-methyl-N-{3-[({2-[(3-{[(3R)-3- methylmorpholin-4-yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2- yl}methanesulfonamide (206) 207

N-methyl-N-{3-[({2-[(3-{[(3R)-3- methylmorpholin-4-yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2- yl}methanesulfonamide (207), trifluoroaceticacid salt 0.00278 208

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N- (1-propylcyclopropyl)benzamide(208) 209

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N- (1-propylcyclopropyl)benzamide(209), trifluoroacetic acid salt 0.00368 210

N-[(1S)-2-hydroxy-1-methylethyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (210) 211

N-[(1S)-2-hydroxy-1-methylethyl]-3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromelhyl)pyrimidin-2- yl}amino)benzamide (211), trifluoroaceticacid salt 0.00106 212

N-methyl-N-[3-({[2-({3-[(3-oxopiperazin-1- yl)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (212) 213

N-methyl-N-[3-({[2-({3-[(3-oxopiperazin-1- yl)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (213), trifluoroacetic acid salt 0.00288 214

N-[3-({[2-{[3-(aminomethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (214) 0.0007 215

N~2~-acetyl-N-[4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)benzyl]glycinamide (215) 0.0006 216

N-{3-[({2-[(4-{[(aminocarbonyl)amino]- methyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (216) 0.0006 217

N-cyclopropyl-2-[4-({4-[({2~ [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)phenyl]acetamide (217) 0.0006 218

N-[3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)benzyl]acetamide (218) 0.0006 219

tert-butyl 4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzoate(219) 0.0006 220

N-{3-[({2-[(5-cyano-2- methylphenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (220) 0.0006 221

N-methyl-N-{3-[({2-[(2-methylpyridin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}methanesulfonamide (221) 0.188 222

N-{3-[({2-[(3-{[(aminocarbonyl)amino]- methyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylrnethanesulfonamide (222) 0.0006 223

N-2-acetyl-N-[3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)benzyl]glycinamide (223) 0.0006 224

N,N-dimethyl-4-{[4-({2- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (224) 0.0006225

N,N-dimethyl-4-{[4-({2- [(methylsuifonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (225) 0.00098 226

N,N-dimethyl-4-{[4-({4-methyl-2- [(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (226) 0.00292 227

N,N-dimethyl-4-{[4-({2-methyl-6- [(melhylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (227) 0.00343 228

N, N-dimethyl-4-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (228) 0.00219229

N,N-dimethyl-4-{[4-{[3- (methylsulfonyl)benzyl]amino}-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (229) 0.00493 230

N,N-dimethyl-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(230) 0.00238 231

N,N-dimethyl-4-({4-[({6-methyl-2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (231) 0.0006 232

N-{3-[({2-[(4-{[(3R,4R)-3,4- difluoropyrrolidin-1-yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (232) 0.00262233

N-[3-(dimethylamino)propyl]-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (233) 0.00133 234

N-(2-hydroxyethyl)-N-methyl-4-({4-{({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (234) 0.00232 235

N-[3-({[2-({4-[(3-fluoropyrrolidin-1- yl)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (235) 0.0006 236

N-{3-[({2-[(4-{[(3S)-3-fluoropyrrolidin-1- yl]carbonyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (236) 0.00141 237

N-methyl-N-[3-({[2-{[4-(pyrrolidin-1- ylcarbonyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (237) 0.00205 238

4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N- [(2R)-tetrahydrofuran-2-ylmethyl]benzamide (238) 0.00125 239

N-[3-({[2-({4-[(4-hydroxypiperidin-1- yl)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (239) 0.0006 240

N-cyclobutyl-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(240) 0.00069 241

N-[1-(hydroxymethyl)-2-methylpropyl]-4- ({4-[{{2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (241) 0.0006 242

N-isopropyl-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(242) 0.001 243

N-(cyclopropylmethyl)-N-methyl-4-({4-[({2-[methyl(methylsulfonyl)amino3pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (243) 0.0021 244

N-(2-hydroxyethyl)-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(244) 0.00111 245

N-[2-(acetylamino)ethyl]-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (245) 0.00262 246

N-[(1-hydroxycyclobutyl)methyl]-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (246) 0.0006 247

N-[3-({[2-({4-[(3-hydroxypiperidin-1- yl)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (247) 0.00063 248

4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N- (pyridin-2-ylmethyl)benzamide(248) 0.00935 249

N-{3-[({2-[(4-{[(3R)-3-hydroxypyrrolidin-1- yl]carbonyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyt]pyridin-2-yl}-N-methylmethane-sulfonamide (249) 0.00191 250

4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N-(1-methylpiperidin-4-yl)benzamide (250) 0.00069 251

N-[2-(dimethylamino)ethyl]-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (251) 0.00121 252

N-(cyclopropylmethyl)-4-({4-[({2-[methyl(methylsulfonyl)amino}pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (252) 0.00148 253

N-[3-({[2-{[4-(azetidin-1 - ylcarbonyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonarriide (253) 0.0006 254

N-methyl-N-[3-({[2-({4-[(3-oxopiperazin-1- yl)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (254) 0.00133 255

N-(3-hydroxypropyl)-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(255) 0.00082 256

N-(3-hydroxy-2,2-dimethylpropyl)-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (256) 0.00157 257

N-[(1R)-1-(hydroxymethyl)butyl]-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (257) 0.0058 258

N-methyl-N-[3-({[2-{[4-(piperidin-1- ylcarbonyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (258) 0.00179 259

N-[2-(dimethylamino)-2-oxoethyl]-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (259) 0.00157 260

N-{3-[({2-[(4-{[(3S)-3-hydroxypiperidin-1- yl]carbonyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethanesulfonamide (260) 0.0023 261

N-methyl-N-{3-[({2-[(4-{[(3S)-3- rnethylmorpholin-4-yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2- yl}methanesulfonamide (261) 0.00113 262

N-cyclopentyl-N-methyl-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (262) 0.0058 263

4-({4-(({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N-(tetrahydro-2H-pyran-3-yl)benzamide (263) 0.00081 264

N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4- ({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (264) 0.0046 265

N-methyl-N-[3-({[2-({4-[(4-methylpiperidin-1-yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2- yl]methanesulfonamide (265) 0.0006 266

N-[3-({[2-({4-[(3.3-difluoropyrrolidin-1- yl)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (266) 0.0006 267

N-{3-[({2-[(4-{[(3S )-3-hydroxypyrrolidin-1-yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (267) 0.00115268

N-[3-({[2-({4-[(3-hydroxy-3- methylpyrrolidin-1 -yl)carbonyl]phenyl}amino)-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N- methylmethane-sulfonamide (268) 0.00262269

N-(2-hydroxyethyl)-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)-N-propylbenzamide (269) 0.00869 270

N-(5-hydroxypentyl)-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(270) 0.00099 271

N-benzyl-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(271) 0.00114 272

N-[3-(([2-({4-[(3-fluoroazetidin-1- yl)carbonyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (272) 0.00264 273

N-{[(1R,2R)-2- (hydroxymethyl)cyclopropyl}methyl}-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin- 3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (273) 0.00269 274

N-[2-(dimethylamino)ethyl]-N-methyl-4- ({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (274) 0.00466 275

N-{3-[({2-[(4-{[(3R)-3-hydroxypiperidin-1- yl]carbonyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (275) 0.00236 276

N-(2-methoxyethyl)-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(276) 0.0006 277

N-(3-methoxypropyl)-N-methyl-4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)arnino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (277) 0.00236 278

N-methyl-N-{3-(({2-[(4-{[(3R)-3- methylmorpholin-4-yl]carbonyl}phenyl)amino]-5- (trlfluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2- yl]methanesulfonamide (278) 0.00664 279

N-{3-[({2-[(4-{[3-(dimethylamino)azelidin-1-yl]carbonyl}phenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (279) 0.00397280

N-{3-[({2-[(4-methoxyphenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (280) 0.0006281

N-{3-[({2-[(3-methoxyphenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (281) 0.0006282

N-{3-[({2-[(3,4-dimethoxyphenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (282) 0.0006283

N-[3-({[2-{[3- (hydroxymethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl)-N-methylmethane-sulfonamide (283) 0.0006 284

N-methyl-N-[3-({[2-{[4- (trifluoromethoxy)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}rnethyl)pyridin-2-yl]methanesulfonamide (284) 0.00183 285

N-methyl-N-[3-({[2-(pyridin-4-ylamino)-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2- yl]methanesulfonamide (285) 0.00127 286

N-{3-[({2-[(3-cyanophenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethanesulfonamide (286) 0.00164287

N-[3-methyl-2-({[2-{[4-(1H-tetrazol-5- yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]methanesulfonamide(287) 0.00195 288

N-methyl-N-{3-[({2-[(3-methylisoxazol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}methanesulfonamide (288) 289

N-methyl-N-{3-[({2-[(3-methylisoxazol-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}methanesulfonamide (289), formic acid salt 0.0182 290

N-methyl-N-{3-[({2-[(4-morpholin-4- ylphenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}methanesulfonamide (290) 291

N-methyl-N-{3-[({2-[(4-morpholin-4- ylphenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}methanesulfonamide (291), hydrochloride salt <0.000595 292

N-{3-[({2-[(6-cyanopyridin-3-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (292),trifluoroacetic acid salt 0.0233 293

N-methyl-N-{3-[({2-[(5-morpholin-4- ylpyridin-2-yl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl]methanesulfonamide (293), trifiuoroacetic acid salt <0.000595 (n=2)294

3-({4-[({6-methyl-2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(294) <0.000595 295

3-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (295) 0.00133 296

3-({4-[({2-methyl-4- [methyl(methylsulfonyl)amino]pyrimidin-5-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(296) 0.00389 297

3-({4-[({3- [melhyl(methylsulfonyl)amino]pyrazin-2- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (297) 0.00226 298

N-{3-[({2-[(4-aminopyrimidin-2-yl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (298) 0.0328 299

N-{3-[({2-[(2-aminopyrimidin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (299) >0.188 300

4-{[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2- yl]amino}-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (300) 0.121 301

N-[3-({[2-{[3-(1- hydroxyethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (301) <0.000595 302

1,1,1-trifluoro-N-[4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)benzyl]methanesulfonamide (302) 0.00100 303

1,1,1-trifluoro-N-[3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)benzyl]methanesulfonamide (303) 0.000727 304

4-methoxy-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(304) 0.000777 305

4-methoxy-3-({4-[({6-methyl-2- [methyl(methylsulfonyl)-amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(305) 0.000646 306

4-methoxy-3-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(306) 0.000696 307

4-methoxy-3-({4-[({3- [methyl(methylsulfonyl)amino)pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(307) 0.00111 308

4-methoxy-3-({4-[({2-methyl-4- [methyl(methylsulfonyl)-amino]pyrimidin-5-yl}methyl)amino]-5- (trifluoromethyl)pyrirnidin-2- yl}amino)benzamide(308) 0.00350 309

4-methyl-3-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(309) 0.00351 310

4-methyl-3-({4-[({2-methyl-4- [methyl(methylsulfonyl)amino]pyrimidin-5-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(310) 0.00504 311

N-{3-[({2-[(4-acetylphenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (311) 0.00100312

N-{3-[({2-[(3-acetylphenyl)amino]-5- (trifluoromethyl)pyrimidin-4-yl}amino)methyl]pyridin-2-yl}-N- methylmethane-sulfonamide (312) 0.00126313

N-methyl-N-{3-[({2-[(3-morpholin-4- ylphenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}methanesulfonamide (313) 0.00202 314

N-methyl-N-[3-({[2-{[4-(1H-tetrazol-5- yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (314) <0.000595 315

N-[3-({[2-{[3-(4,5-dihydro-1,3-oxazol-2- yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (315) 0.000914 316

N-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(316) 0.000965 317

N-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(317) <0.000595 318

N-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(318), hydrochloride salt 0.00179 319

N-[3-({[2-{[4- (hydroxymethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (319) <0.000595 320

2-fluoro-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(320), formic acid salt <0.000595 321

4-{[4-({3-[(difluoromethyl)(methyl- sulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzoate (321) 0.119(0.0159-0.883 n=2) 322

3-fluoro-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(322), formic acid salt <0.000595 323

N-[3-({[2-{[4-(1-hydroxy-1- methylethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (323) 0.00150 324

N-[3-({[2-{[4-(1-hydroxy-1- methylethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]-N-methylmethanesulfonamide (324) 0.00187 325

N-[2-({[2-{[4-(1-hydroxy-1- methylethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl)amino}methyl)pyridin-3-yl]-N-methylmethane-sulfonamide (325) 0.00266 326

N-[3-({[2-{(4-(1-hydroxy-1- methylethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyrazin-2-yl]-N-methylmethane-sulfonamide (326) 0.00162 327

2-fluoro-4-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(327), formic acid 0.00169 328

N-[3-({[2-{[4-(1- hydroxyethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]-N-methylmethanesulfonamide (328) 0.000619 329

N-[2-({[2-{[4-(1- hydroxyethyl)phenyl}amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-3-yl)-N-methylmethane-sulfonamide (329) 0.000914 330

N-[3-({[2-{[4-(1- hydroxyethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyrazin-2-yl]-N-methylmethane-sulfonamide (330) 0.000750 331

2-fluoro-4-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(331), hydrochloride salt 0.00177 332

2-fluoro-4-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(332), formic acid salt 0.000863 333

2-fluoro-4-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (333) 0.00214334

2-methyl-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl)amino)benzamide(334) <0.000595 (n=2) 335

2-methyl-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(335), hydrochloride salt <0.000595 (n=2) 336

2-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl)amino)benzamide(336) <0.000595 337

2-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(337), hydrochloride salt <0.000595 338

2-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(338) <0.000595 339

2-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(339), hydrochloride salt <0.000595 340

2-methyl-4-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (340)<0.000595 341

3-methyl-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(341) <0.000595 342

3-methyl-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(342), hydrochloride salt 0.00103 343

3-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(343) 0.000993 344

3-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(344) 0.000900 345

3-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(345), hydrochloride salt 0.000981 346

3-methyl-4-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (346) 0.000886347

N-[3-({{2-{[4- (isopropoxymethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (347) 0.00215 348

N-[3-({[2-{[4-(chloromethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (348) 0.00155 349

N-methyl-N-[3-({[2-{[4-(morpholin-4- ylmethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesuifonamide (349) <0.000595 350

4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}oxy)benzamide (350) 0.0637 351

N-[3-({[2-({4-[(1R)-1- aminoethyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyrazin-2-yl]-N-methylmethane-sulfonamide (351), hydrochloride salt 0.000616 352

N-[2-({[2-({4-[(1R)-1- aminoethyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-3-yl]-N-methylmethane-sulfonamide (352), hydrochloride salt <0.000595 353

N-[3-({[2-({4-[(1R)-1- aminoethyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]-N-methylmethanesulfonamide (353), hydrochloride salt <0.000595 354

N-[3-({[2-({4-[(1R)-1- aminoethyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (354), hydrochloride salt <0.000595 355

N-[3-({[2-({4-((1S)-1- aminoethyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyrazin-2-yl]-N-methylmethane-sulfonamide (355), hydrochloride salt <0.000595 356

N-[2-({[2-({4-[(1S)-1- aminoethyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-3-yl]-N-methylmethane-sulfonamide (356), hydrochloride salt 0.000593 357

2-chloro-4-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (357) 0.00147358

2-chloro-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(358) <0.000595 359

2-chloro-4-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(359) <0.000595 360

2-chloro-4-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(360) <0.000595 361

3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)-N- piperidin-4-ylbenzamide (361),hydrochloride salt 0.00870 362

N-[2-({[2-({4-[(1R)-1- aminoethyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]-N-methylmethanesulfonamide (362), hydrochloride salt <0.000595 363

N-[2-({[2-({4-[(1S)-1- aminoethyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]-N-methylmethanesulfonamide (363), hydrochloride salt <0.000595 364

N-[3-({[2-({4-[(1S)-1- aminoethyl]phenyl}amino)-5-(trifiuoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (364). hydrochloride salt 0.000644 365

N-[3-({[2-({4-[(1S)-1- aminoethyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]-N-methylmethanesulfonamide (365), hydrochloride salt 0.000976 366

N-[3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)phenyl]acetamide (366) <0.000595 367

N-methyl-N-[3-({[2-{[3-(3-methyl-2-oxoimidazolidin-1-yl)phenyl]amino}-5- (trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2- yl]methanesulfonamide (367) 0.00164 368

3-fluoro-N-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(368) <0.000595 369

3-fluoro-N-methyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(369), hydrochloride salt 0.00149 370

2-fluoro-N-methyl-4-({4-(({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(370) 0.000600 371

N-(3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)phenyl]propanamide (371) 0.00194 372

5-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)pyridine-2-carboxamide (372),formic acid salt 0.00400 373

4-fluoro-3-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(373) 0.00749 374

4-fluoro-3-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (374) 0.0155375

4-fluoro-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl)amino)benzamide(375) 0.00629 376

5-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}pyridine-2-carboxamide(376), formic acid salt 0.00815 377

5-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)pyridine-2-carboxamide (377),formic acid salt 0.0153 378

4-fluoro-3-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(378) 0.00194 379

2-fluoro-5-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzamide (379),hydrochloride salt 0.00478 380

2-fluoro-5-({4-[{{2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(380), hydrochloride salt 0.00160 381

2-fluoro-5-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(381), hydrochloride salt 0.00455 382

2-fluoro-5-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(382), hydrochloride salt 0.0107 383

N-{3-[({2-[(4-{[(2- hydroxyethyl)amino]methyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (383) <0.000595 384

N-[3-({[2-({4- [(isopropylamino)methyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (384) <0.000595 385

N-[3-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)phenyl]acetamide (385) 0.00144 386

N-[3-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)phenyl]acetamide (386) 0.00165 387

N-(3-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}phenyl)acetamide (387)0.00295 388

N-{3-[({2-((4-{[(2- methoxyethyl)amino]methyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (388) <0.000595 389

N-[3-({[2-{[4-({[2-hydroxy-1- (hydroxymethyl)ethyl]amino}methyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4-yl]amino}methyl)pyridin-2-yl]-N- methylmethane-sulfonamide (389)<0.000595 390

N-{3-[({2-[(4-cyano-3- hydroxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethane-sulfonamide (390) 0.000746 391

N-{3-[({2-[(4-cyano-3- hydroxyphenyl)amino]-5-(trifluoromethyl)pyrlmldin-4- yl}amino)methyl]pyrazin-2-yl}-N-methylmethane-sulfonamide (391), hydrochloride salt 0.00124 392

N-{3-[({2-[(4-cyano-3- hydroxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]phenyl}-N-methylmethanesulfonamide (392) 0.00451 393

2-hydroxy-4-{[4-{[3- (methylsulfonyl)benzyl]amino}-5-(trifluoromethyl)pyrimidin-2- yl]amino}benzonitrile (393) 0.00741 394

2-hydroxy-4-({4-[({2- [methyl(methylsulfonyl)amino)pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(394), formic acid salt <0.000595 395

2-hydroxy-4-({4-(({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(395), formic acid salt 0.000849 396

2-hydroxy-4-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}bertzamide (396), formicacid salt 0.00313 397

N-2-acetyl-N-[3-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)phenyl]glycinamide (397) 0.00151 398

N~2~-acetyl-N-[3-({4-[({3- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)phenyl]glycinamide (398) 0.00218 399

N-2-acetyl-N-(3-{[4-({3- [methyl(methylsulfonyl)amino]benzyl}amino)-5-(trifluoromethyl)pyrimidin-2- yl]amino}phenyl)glycinamide (399)0.00557 400

N,2-dimethyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl)methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(400), hydrochloride salt 0.000660 401

N,3-dimethyl-4-({4-[({3- [methyl(methylsulfonyl)amino]pyrazin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(401), hydrochloride salt 0.00117 402

N,2-dimethyl-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(402), hydrochloride salt <0.000595 403

N,3-dimethyl-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino)-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(403), hydrochloride salt 0.00109 404

4-({4-[({4- [methyl(methylsulfonyl)amino]pyridin-2- yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2- yl}amino)benzamide (404), formic acid salt0.00207 405

3-methyl-4-({4-[({4- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(405), formic acid salt 0.0173 406

2-methyl-4-({4-[({4- [methyl(methylsulfonyl)amino]pyridin-2-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2- yl}amino)benzamide(406), formic acid salt 0.000784 407

N′-hydroxy-4-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)benzenecarboximidamide (407), formic acid salt <0.000595 408

N′-hydroxy-3-({4-[({2- [methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5- (trifluoromethyl)pyrimidin-2-yl}amino)benzenecarboximidamide (408), formic acid salt 0.00229 409

N-[3-({[2-{[4-(2,2-dimethyl-1,3-dioxolan-4- yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyrazin-2-yl]-N-methylmethane-sulfonamide (409) 0.00475 410

N-[3-({[2-{[4-(2,2-dimethyl-1,3-dioxolan-4- yl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl)amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (410) 0.00119 411

N-[3-({[2-{[4-(1,2- dihydroxyethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyrazin-2-yl]-N-methylmethane-sulfonamide (411), hydrochloride salt 0.000941 412

N-[3-({[2-{[4-(1,2- dihydroxyethyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]-N-methylmethane-sulfonamide (412), hydrochloride salt <0.000595 413

N-{3-[({2-[(4-{[(2-hydroxy-2- methylpropyl)amino]methyl}phenyl)amino]-5-(trifluoromethyl)pyrimidin-4- yl}amino)methyl]pyridin-2-yl}-N-methylmethanesulfonamide (413) <0.000595 414

N-methyl-N-[3-({[2-({4- [(methylamino)methyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)pyridin-2-yl]methanesulfonamide (414), hydrochloride salt <0.000595 415

N-methyl-N-[2-({[2-({4- [(methylamino)methyl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-4- yl]amino}methyl)phenyl]methanesulfonamide(415), hydrochloride salt <0.000595

We claim:
 1. A method of making a compound of Formula (1), the methodcomprising:

reacting a compound of Formula (C3):

with a compound of Formula (B5):

thereby providing the compound of Formula (1).
 2. The method of claim 1,wherein the reaction of the compound of Formula (C3) and the compound ofFormula (B5) is performed in the presence of a base.
 3. The method ofclaim 2, wherein the base is diethylamine (DIEA).
 4. The method of claim1, wherein the reaction of the compound of Formula (C3) and the compoundof Formula (B5) is performed for 20 hours.
 5. The method of claim 1,wherein the reaction is performed in the presence of a solvent.
 6. Themethod of claim 5, wherein the solvent is 1,2-dichloroethane(DCE):t-BuOH.
 7. The method of claim 6, wherein the 1,2-dichloroethane(DCE):t-BuOH is 1:1 vol:vol.
 8. The method of claim 1, wherein thetemperature is 80° C.
 9. The method of claim 1, wherein isolating thecompound of Formula (1) comprises decreasing the temperature of thereaction mixture to ambient temperature.
 10. The method of claim 9,wherein the ambient temperature is 25° C.
 11. The method of claim 9,wherein isolating the compound of Formula (1) comprises treating thereaction of the compound of Formula (C3) and the compound of Formula(B5) with EtOAc.
 12. The method of claim 9, wherein the reaction of thecompound of Formula (C3) and the compound of Formula (B5) is washed withwater.
 13. The method of claim 9, wherein the reaction of the compoundof Formula (C3) and the compound of Formula (B5) is dried over MgSO₄.14. The method of claim 9, wherein isolating the compound of Formula (1)comprises filtration.